ES2910108T3 - Histone methyltransferase inhibitors - Google Patents

Abstract

A compound of formula (I): **(See formula)** in which: Z1 and Z2 are independently C (when R2 or R3 are attached to them), CH or N; alk is alkylene in which one or two carbon atoms of the alkylene chain are optionally replaced by NR, O, S or SO2 (where R is hydrogen or alkyl), and the alkylene chain is substituted by one or two substituents independently selected from halo, haloalkyl, haloalkoxy, hydroxy, and alkoxy, and wherein -alk-R1 is attached to carbon (a) or (b); where alk in -(alk)-R1 is -(CH2)2-*, -(CH2)3-*, -(CH2)4-*, -CH2CH(CH3)CH2-*, *-CH2CH(CH3 )CH2 -, -O-(CH2)-*, -O- (CH2)2-*, -O-(CH2)3-*, -OCH2CH(F)CH2-*, -OCH2CH(OCH3)CH2-* , or -OCH2CH(OCF3)CH2-*, where * indicates the point of attachment to -R1; R1 is -NR6R7 (wherein R6 and R7 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl or haloalkoxyalkyl), unsubstituted heterocyclyl, heterocyclyl substituted with 1, 2 or 3 of Ra, Rb and Rc where Ra, Rb and Rc are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, alkylcarbonyl, and haloalkylcarbonyl, or spiroheterocycloamino in which a nitrogen atom of the spiroheterocycloamino is bonded to alk; R2 is hydrogen, alkyl, cycloalkyl, halo, hydroxy, alkoxy, haloalkoxy, or cyano; R3 is hydrogen, alkyl, halo, alkoxy, alkylamino, dialkylamino, or cyano; R4 is alkyl (optionally substituted with one to nine deuterium), or NReRf (where Re is hydrogen or alkyl and Rf is hydrogen, alkyl, deuterated alkyl, alkylthioalkyl, acyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cyanoalkyl, carboxyalkyl, alkoxycarbonylalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl), wherein cycloalkyl, aryl, heteroaryl, and heterocyclyl alone or as part of cycloalkylalkyl, aralkyl, heteroaralkyl, and heterocyclylalkyl at Rf is unsubstituted or substituted with 1, 2, or 3 of Rg, Rh, and Ri, wherein Rg, Rh, and Ri are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, cyano, carboxy, alkoxycarbonyl, and haloalkoxy, and wherein the alkylene of the aralkyl, heteroaralkyl, heterocyclylalkyl and cycloalkylalkyl at Rf is optionally substituted with one to nine deuteriums; X is carbon or nitrogen; and ring B is phenyl, 5- or 6-membered cycloalkyl, spirocycloalkyl, spiroheterocycloamino, or saturated 5-, 6-, or 7-membered heterocyclyl, wherein each of the ring(s) of ring B is unsubstituted or substituted with 1, 2 , 3 or 4 of Rj, Rk, Rl and Rm wherein Rj, Rk, Rl and Rm are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl and haloalkoxy; or one of its pharmaceutically acceptable salts.

Description

DESCRIPTION

Histone methyltransferase inhibitors

Disclosure field

The present disclosure provides certain angular tricyclic compounds that are inhibitors of histone methyltransferases G9a and/or GLP and are therefore useful for the treatment of diseases treatable by inhibition of G9a and/or GLP such as cancers and hemoglobinopathies (eg. , beta-thalassemia and sickle cell disease). Pharmaceutical compositions containing such compounds are also provided.

Background

Chromatin modification plays an essential role in transcriptional regulation. These modifications, including DNA methylation, histone acetylation, and histone methylation, are important in a variety of biological processes, including protein production and cell differentiation, and are emerging as attractive drug targets in various human diseases. Two particular enzymes associated with histone methylation are G9a and GLP, also known as EHMT2 and EHMT1 (euchromatic histone-lysine N-methyltransferase 2 and 1). G9a and GLP are the major enzymes for monomethylation and dimethylation at Lys 9 of histone H3 (H3K9me1 and H3K9me2), and exist predominantly as a heteromeric G9a-GLP complex that appears to be a functional H3K9 methyltransferase in vivo. Structurally, both G9a and GLP are composed of a catalytic SET domain, an ankyrin repeat-containing domain (involved in protein-protein interactions), and nuclear localization signals in the N-terminal region. The SET domain is responsible for the addition of methyl groups on H3, while ankyrine repeats have been shown to represent mono- and dimethyl lysine binding regions. The G9a-GLP complex, therefore, is not only capable of methylating histone tails, but can also recognize this modification and may function as a framework for the recruitment of other target molecules to chromatin [see Shinkai et al. ., Genes Dev. 2011 Apr 15; 25(8):781-8. doi: 10.1101/gad.2027411. H3K9 methyltransferase G9a and the related molecule GLP; and Shankar et al., Epigenetics. January 2013; 8(1):16-22. doi:10.4161/epi.23331. G9a, a multipotent regulator of gene expression].

Many studies have reported that G9a and GLP play critical roles in various biological processes. Several reports have highlighted its link to a variety of cancers [see Cascielle et al., Front Immunol. September 25, 2015; 6:487. doi: 10.3389/fimmu.2015.00487. Functional Role of G9a Histone Methyltransferase in Cancer]. It is upregulated in hepatocellular carcinoma, B-cell acute lymphoblastic leukemia, and lung cancers. Furthermore, elevated expression of G9a in aggressive lung cancer correlates with poor prognosis, while its deletion in highly invasive lung cancer cells suppressed metastasis in an in vivo mouse model. In prostate cancer cells (PC3), G9a deletion caused significant morphological changes and cell growth inhibition [see Liu et al., J. Med Chem. 2013 Nov 14; 56 (21): 8931-42. doi: 10.1021/jm401480r. Epub 2013 Oct 31. Discovery of an in vivo chemical probe of the lysine methyltransferases G9a and GLP; and Sweis et al., ACS Med Chem Lett. January 2, 2014; 5(2): 205-9. doi: 10.1021/ml400496h. eCollection 2014. Discovery and development of potent and selective inhibitors of histone methyltransferase g9a]. Loss of G9a has been shown to impair DNA damage repair and improve the sensitivity of cancer cells to radiation and chemotherapy. See Yang et al., Proc. Natl. Acad. Sci. USA, 2017, doi:10.1073/pnas.1700694114.

Interestingly, recent studies have also shown that inhibition of G9a and GLP by genetic depletion or pharmacological intervention increased fetal hemoglobin (HbF) gene expression in erythroid cells [see Krivega et al., Blood. July 30, 2015; 126 (5): 665-72. Inhibition of G9a methyltransferase stimulates fetal hemoglobin production by facilitating LCR/Y-globin looping; and Renneville et al., Blood. 2015 Oct 15;126(16):1930-9. EHMT1 and EHMT2 inhibition induces fetal hemoglobin expression]. Induction of the fetal globin gene would be potentially therapeutically beneficial for the disease of hemoglobinopathies, including beta-thalassemia and sickle cell disease, in which normal p-globin production is impaired, a component of adult hemoglobin [see Sankaran et al., Cold Spring Harb Perspect Med. Jan 2013; 3(1): a011643. doi:10.1101/cshperspect.a011643. The Switch from Fetal to Adult Hemoglobin]. In addition, G9a or GLP inhibitions may potentiate other clinically used therapies, such as hydroxyurea or HDAC inhibitors. These agents may act, at least in part, by increasing Y-globin gene expression through different mechanisms [see Charache et al., Blood. May 15, 1992; 79(10): 2555-65. Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia]. Therefore, there is a need to develop small molecules that are capable of inhibiting the activity of G9a and/or GLP. The compounds of the present disclosure meet this and related needs.

US 2015/274660 (Pliushchev, Marina A.) is directed to compounds, pharmaceutical compositions, and methods for treating cancer, inflammation, or autoimmune disease in a subject, or for inhibiting histone methyltransferase G9a.

Chen Wei-Lin et al. "Discovery, design and synthesis of 6H-anthra[1,9-cd]isoxazole-6-one scaffold as G9a inhibitor through a combination of shape-based virtual screening and structure-based molecular modification", Bioorganic & Medicinal Chemistry, vol. 24, no. 22, September 30, 2016, pages 6102-6108, is directed to the synthesis and characterization of compounds for use as G9a inhibitors.

WO 2015/192981 (Foundation for Applied Medical Research) is directed to compounds for use as dual inhibitors of histone methyltransferases and DNA methyltransferases.

Summary

In one aspect there is provided a compound of Formula (I):

in which:

Z ¹ and Z ² are independently C (when R ² or R ³ are attached to them), CH or N;

alk is alkylene in which one or two carbon atoms of the alkylene chain are optionally replaced by NR, O, S or SO ² (wherein R is hydrogen or alkyl), and the alkylene chain is optionally substituted by one or two substituents independently selected from halo, haloalkyl, haloalkoxy, hydroxy, and alkoxy, and wherein -alk-R ¹ is attached to carbon (a) or (b);

where alk in -(alk)-R ¹ is -(CH ² ) ² -*, -(CH ² ) ³ -*, -(CH ² ) ⁴ -*, -CH ² CH(CH ³ )CH ² -*, *-CH ² CH(CH ³ )CH ² -, -O-(CH ² )-*, -O-(CH ² ) ² -*, -O-(CH ² ) ³ -*, -OCH ² CH(F)CH ² -*, -OCH ² CH(OCH ³ )CH ² -*, or -OCH ² CH(OCF ³ )CH ² -^, where * indicates the point of attachment to -R ¹ ;

R ¹ is -NR ⁶ R ⁷ (wherein R ⁶ and R ⁷ are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl or haloalkoxyalkyl), unsubstituted heterocyclyl, heterocyclyl substituted with 1, 2 or 3 of R ^a , R ^b and R ^c in which R ^a , R ^b and R ^c are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, alkylcarbonyl and haloalkylcarbonyl, or spiroheterocycloamino in which one nitrogen atom of the spiroheterocycloamino is bonded to alk;

R ² is hydrogen, alkyl, cycloalkyl, halo, hydroxy, alkoxy, haloalkoxy, or cyano;

R ³ is hydrogen, alkyl, halo, alkoxy, alkylamino, dialkylamino, or cyano;

R ⁴ is alkyl (optionally substituted with one to nine deuterium), or NR ^e R ^f (where R ^e is hydrogen or alkyl and R ^f is hydrogen, alkyl, deuterated alkyl, alkylthioalkyl, acyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cyanoalkyl, carboxyalkyl, alkoxycarbonylalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl), wherein cycloalkyl, aryl, heteroaryl, and heterocyclyl alone or as part of cycloalkylalkyl, aralkyl, heteroaralkyl and heterocyclylalkyl at R ^f is unsubstituted or substituted with 1, 2 or 3 of R ^g , R ^h and R ⁱ , where R ^g , R ^h and R ⁱ are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, cyano, carboxy, alkoxycarbonyl, and haloalkoxy, and wherein the alkylene of the aralkyl, heteroaralkyl, heterocyclylalkyl, and cycloalkylalkyl at ^Rf is optionally substituted with one to nine deuteriums;

X is carbon or nitrogen; Y

ring B is phenyl, 5- or 6-membered cycloalkyl, 5-, 6-, or 7-membered saturated spirocycloalkyl, spiroheterocycloamino, or heterocyclyl, wherein each of the ring(s) of ring B is unsubstituted or substituted with 1,2, 3 or 4 of R ^j , R ^k , R ¹ and R ^m wherein R ^j , R ^k , R ¹ and R ^m are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl and haloalkoxy; either

one of its pharmaceutically acceptable salts.

In a second aspect, this disclosure is directed to a pharmaceutical composition comprising a compound of Formula (I) (or any of its embodiments described herein), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

In a third aspect, this disclosure relates to a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease treatable by inhibition of G9a. In one embodiment, the disease may be a hemoglobinopathy, such as beta-thalassemia and sickle cell disease. See Krivega et al., Blood, 2015; 126(5):665-72 and Renneville et al., Blood. October 15, 2015; 126(16): 1930-9. In a second embodiment, the disease may be a cancer or tumor, eg, a cancer or tumor in which G9a may be overexpressed. Examples of such cancers and tumors include, but are not limited to: colorectal cancer, osteosarcoma cancer, acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); adrenocortical carcinoma, Kaposi's sarcoma (soft tissue sarcoma); an AIDS-related lymphoma (lymphoma); a primary CNS lymphoma; an anal cancer; a gastrointestinal carcinoid tumor; an astrocytoma; an atypical teratoid/rhabdoid tumor; a basal cell carcinoma of the skin; a cancer of the bile ducts; bladder cancer; a bone cancer (includes Ewing's sarcoma and osteosarcoma and malignant fibrous histiocytoma); a brain tumor; a breast cancer; a bronchial tumor, a Burkitt's lymphoma; a heart tumor; a embryonal tumor (brain cancer); a germ cell tumor (brain cancer); a primary CNS lymphoma; cervical cancer; a cholangiocarcinoma; a chordoma; a chronic lymphocytic leukemia (CLL); a chronic myelogenous leukemia (CML); a chronic myeloproliferative neoplasm; colorectal cancer; a craniopharyngioma (brain cancer); a cutaneous T-cell lymphoma; a ductal carcinoma in situ (DCIS); endometrial cancer (uterine cancer); an ependymoma (brain cancer); an esophageal cancer; an esthesioneuroblastoma; Ewing's sarcoma (bone cancer); extracranial germ cell tumor; extragonadal germ cell tumor; eye cancer; intraocular melanoma; a retinoblastoma; fallopian tube cancer; a fibrous histiocytoma of bone; gallbladder cancer; a gastric (stomach) gastrointestinal stromal tumor (GIST) (soft tissue sarcoma); a CNS germ cell tumor (brain cancer); an extracranial germ cell tumor; an extragonadal germ cell tumor; an ovarian germ cell tumor; testicular cancer; gestational trophoblastic disease; a hairy cell leukemia; head and neck cancer; hepatocellular (liver) cancer; a histiocytosis, a Langerhans cell; Hodgkin's lymphoma; hypopharyngeal cancer (cancer of the head and neck); an intraocular melanoma; an islet cell tumor; a pancreatic neuroendocrine tumor; kidney (renal cell) cancer; a Langerhans cell histiocytosis; cancer of the larynx (cancer of the head and neck); a leukemia; a cancer of the lip and oral cavity (cancer of the head and neck); lung cancer (non-small cell and small cell); a lymphoma; a male breast cancer; a melanoma; a Merkel cell carcinoma (skin cancer); to mesothelioma; a malignant mesothelioma; metastatic squamous cell carcinoma of the neck with an occult primary (head and neck cancer); a midline tract carcinoma involving the NUT gene; mouth cancer (cancer of the head and neck); multiple syndromes of endocrine neoplasia; multiple myeloma/plasma cell neoplasms; a mycosis fungoides (lymphoma); a myelodysplastic syndrome, a myelodysplastic/myeloproliferative neoplasm; a cancer of the nasal cavity and paranasal sinus (cancer of the head and neck); a cancer of the nasopharynx (cancer of the head and neck); a nasopharyngeal cancer - neuroblastoma; a non-Hodgkin's lymphoma; an oral cancer; lip and oral cavity cancer and oropharyngeal cancer (cancer of the head and neck); ovarian cancer; pancreatic cancer; a papillomatosis; a paraganglioma; a cancer of the paranasal sinus and nasal cavity (cancer of the head and neck); parathyroid cancer; penile cancer; to pharyngeal cancer (cancer of the head and neck); a pheochromocytoma; a pituitary tumor; a pleuropulmonary blastoma; a primary CNS lymphoma; a primary peritoneal cancer; prostate cancer; a rectal cancer; a rhabdomyosarcoma (soft tissue sarcoma); salivary gland cancer (head and neck cancer); a salivary gland tumor; a vascular tumor (soft tissue sarcoma); a uterine sarcoma; a Sezary syndrome (lymphoma); small intestine cancer; a squamous cell carcinoma; a skin cancer; a squamous cell cancer of the neck with an occult primary, metastatic (cancer of the head and neck); a cutaneous T-cell lymphoma; throat cancer (head and neck cancer); a nasopharyngeal cancer; an oropharyngeal cancer; hypopharyngeal cancer; a thymoma and a thymic carcinoma; to thyroid cancer; urethral cancer; a vaginal cancer; a vascular tumor (soft tissue sarcoma); vulvar cancer; a myelodysplastic syndrome (MDS); and a Wilms tumor. Thus, the terms "cancer cell", "cancer cell" or "tumor cell", as mentioned herein, include a cell affected by or related to any of the conditions identified above. See Cascielle et al., Front. Immunol. 2015; 6:487, Agarwal et al., Cancer Letters 2016:467 and Zhang et al., Oncotarget 2015, 6(5):2917. In a third embodiment, treating a cancer and/or tumor comprises increasing tumor-free survival and/or reduce tumor mass and/or retard tumor growth. In a fourth embodiment, the disease may be a cancer predisposition syndrome, such as Cowden's syndrome. See You et al., Cancer Cell, 2012; 22(1): 9-20. In a fifth embodiment, the disease may be an inflammatory and/or autoimmune disease, such as intestinal inflammation, arthritis, atherosclerosis, multiple sclerosis, myasthenia gravis, Crohn's disease, graft-versus-host disease, psoriasis, granulomatous colitis, lymphocytic colitis, collagenous colitis, ulcerative colitis, celiac disease, subepidermal bullous disorders, systemic lupus erythematosus, discoid lupus erythematosus, cutaneous lupus, dermatomyositis, polymyositis, Sjogren's syndrome, primary biliary cirrhosis, chronic active hepatitis, chronic fatigue syndrome, and vasculitis. See Antignano et al., J. Clin. Invest. 2014, 4(5): 1945-55. In a sixth embodiment, the disease may be a metabolic disease, such as diabetes and/or obesity. See Wang et al., EMBO J. 2013; 32(1):45-59. In a seventh embodiment, the disease may be related to skeletal muscle development and regeneration. See Ling et al., Proc. Natl. Acad. Sci. USA, 2012; 109(3): 841-6. In an eighth embodiment, the disease may be a viral disease, such as HIV-1 (human immunodeficiency virus 1) and HBV (hepatitis B virus). See Imai et al., J. Biol. Chem. 2010; 285(22): 16538-45 and Merkling et al., PLoS Pathog. 2015; 11(4). The compounds and compositions described herein may be administered with one or more additional therapeutic agents including, but not limited to, anticancer agents and antiviral agents. See, for example, Front Immunol. 2015; 6:487; Agarwal et al., Cancer Lett. 2016:467 and Zhang et al., Oncotarget 2015, 6(5):2917.

This disclosure also relates to a method of inhibiting G9a and/or GLP, comprising contacting a cell with a therapeutically effective amount of a compound of Formula (I) (or any of its embodiments described herein), or one of its pharmaceutically acceptable salts. In some embodiments, the cell suffers from one or more of the diseases mentioned in the third aspect herein.

Detailed description

Definitions:

Unless otherwise indicated, the following terms used in the specification and claims are defined for the purposes of this Application and have the following meaning:

"Alkyl" means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, for example, methyl, ethyl, n-propyl, 2-propyl (isopropyl), n- butyl, sec-butyl, iso-butyl, tert-butyl, pentyl (straight or branched chain), hexyl (straight or branched chain), and the like.

"Alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, unless otherwise indicated, for example, methylene, ethylene, propylene, 1 -methylpropylene, 2-methylpropylene, butylene, pentylene and the like.

"Alkylthioalkyl" means a radical -RSR' in which R and R' are independently alkyl as defined above.

"Alkoxy" means an -OR radical in which R is alkyl as defined above, eg, methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like.

"Alkoxyalkyl" means alkyl as defined above that is substituted with one or two alkoxy groups as defined above, eg, methoxyethyl, ethoxyethyl, methoxypropyl, and the like.

"Alkylcarbonyl" or "Acyl" means a radical -COR where R is alkyl as defined above, eg, methylcarbonyl, ethylcarbonyl, and the like.

"Alkoxycarbonyl" means a -C(=O)OR radical in which -R is alkyl as defined above, eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, and the like.

"Alkoxycarbonylalkyl" means alkyl as defined above that is substituted with one or two alkoxycarbonyl groups as defined above, eg, methoxycarbonylethyl, ethoxycarbonylethyl, methoxycarbonylpropyl, and the like.

"Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms, for example, phenyl or naphthyl.

"Aralkyl" means a -(alkylene)-R radical in which R is aryl as defined above, eg, benzyl, phenethyl, and the like.

"Aminoalkyl" means a radical -(alkylene)-NR'R" in which R' and R" are independently hydrogen or alkyl as defined above.

"Alkylamino" means a radical -NHR' where R' is alkyl as defined above.

"Cycloalkyl" means a cyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms, unless otherwise indicated, eg, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the like.

"Cycloalkylalkyl" means a -(alkylene)-R radical in which R is cycloalkyl as defined above, eg, cyclopropylmethyl, cyclohexylmethyl, and the like.

"Cycloalkenyl" means a cyclic hydrocarbon radical of three to ten carbon atoms containing a double bond, unless otherwise indicated, eg, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like.

"Cyanoalkyl" means an alkyl radical as defined above that is substituted with a cyano group. "Carboxy" means a -C(=O)Oh group.

"Carboxyalkyl" means an alkyl radical as defined above that is substituted with a carboxy group. "5- or 6-membered cycloalkenyl" means a cyclic hydrocarbon radical of five or six carbon atoms containing one double bond.

"Deuterated alkyl" means an alkyl radical as defined above that is substituted with one, two or three deuterium atoms.

"Dialkylamino" means a radical -NRR' in which R and R' are alkyl as defined above.

"Halo" or "halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

"Haloalkyl" means an alkyl radical as defined above, which is substituted with one or more halogen atoms, such as from one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, for example, - CH ² Cl, -CF ³ , -CHF ² , -CH ² CF ³ , -CF ² CF ³ , -CF(CH ³ ) ² and the like. When the alkyl is substituted only with fluorine, it may be referred to in this application as fluoroalkyl.

"Haloalkoxy" means an -OR radical in which R is haloalkyl as defined above, eg, -OCF ³ , -OCHF ² , -OCH ² F, and the like. When the haloalkyl of a haloalkoxy is an alkyl substituted only with fluorine, the haloalkoxy is referred to in this application as fluoroalkoxy.

"Haloalkoxyalkyl" means alkyl as defined above that is substituted with one or two haloalkoxy groups as defined above, eg, trifluoromethoxyethyl, 2,2,2-trifluoroethoxyethyl, and the like.

"Haloalkylcarbonyl" means a -COR radical in which R is haloalkyl as defined above, eg, trifluoromethylcarbonyl, pentafluoroethylcarbonyl, and the like.

"Hydroxyalkyl" means alkyl as defined above that is substituted with one or two hydroxy groups as defined above, eg, hydroxymethyl, hydroxyethyl, 1,3-dihydroxypropyl, and the like.

"Halocycloalkyl" means a cycloalkyl group as defined above that is substituted with one, two or three halogens as defined above, eg, 2,2-difluorocyclopropyl and the like.

"Heterocyclyl" means a monovalent saturated or unsaturated monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatoms independently selected from N, O and S(O) ⁿ , where n is a integer from 0 to 2, and the remaining ring atoms are C, unless otherwise indicated. In addition, one or two carbon atoms in the heterocyclyl ring may optionally be replaced by a -C(=O)- group. More specifically, the term "heterocyclyl" includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, dihydropyranyl, thiomorpholino, and the like. When the heterocyclyl ring is unsaturated, it may contain one or two double bonds in the ring, as long as the ring is not aromatic. When the heterocyclyl group contains at least one nitrogen atom (eg, pyrrolidine, piperidine, piperazine, and oxazolidine), the heterocyclyl ring may also be referred to herein as heterocycloamino and is a subset of the heterocyclyl group. When the heterocyclyl ring has no double bond, it is referred to herein as saturated heterocyclyl.

"Heterocyclylalkyl" or "heterocycloalkyl" means a -(alkylene)-R radical in which R is a heterocyclyl ring as defined above, eg, tetrahydrofuranylmethyl, piperazinylmethyl, morpholinylethyl, and the like.

"5-, 6-, or 7-membered heterocycloalkenyl or heterocyclylalkenyl" means a cyclic hydrocarbon radical of five, six, or seven carbon atoms containing a double bond and in which one or two carbon atoms are independently replaced by N, O, or S (OR) ⁿ where n is an integer from 0 to 2.

"Heteroaryl" means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms, unless otherwise indicated, in which one or more (in one embodiment, one, two or three) ring atoms are heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like. When the heteroaryl ring contains 5 or 6 ring atoms, it is also referred to herein as 5- or 6-membered heteroaryl.

"Heteroaralkyl" means a -(alkylene)-R radical in which R is heteroaryl as defined above, eg, pyridinylmethyl and the like. When the heteroaryl ring in heteroaralkyl contains 5 or 6 ring atoms, the heteroaralkyl is also referred to herein as 5- or 6-membered heteroaralkyl.

"Oxo" means a =(O) radical. As would be apparent to one skilled in the art, "carbonyl" refers to an oxo radical attached to a carbon atom, ie, -C(=O)-.

"Spiroheterocycloamino" means a saturated bicyclic ring having from 7 to 10 ring atoms in which one, two or three ring atoms are heteroatoms selected from N, N-oxide, O and S(O) ⁿ , in the that n is an integer from 0 to 2, with C being the remaining ring atoms, provided that at least one ring atom is N, and the rings are connected through a single atom. The connecting atom is also called a spiroatom and is most often a quaternary carbon ("spirocarbon").

"Spirocycloalkyl" means a saturated bicyclic ring having 7 to 10 ring carbon atoms in which the rings are connected through a single atom. The connecting atom is also called a spiroatom and is most often a quaternary carbon ("spirocarbon").

One skilled in the art will recognize that when ring B is cycloalkyl, heterocyclyl, or spirocycloalkyl, the carbon atoms in these rings that are shared with the adjacent ring (ie, the ring substituted with R ⁴ in Formula I) are sp carbons. ² .

The present disclosure also includes polymorphic forms and deuterated forms of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include:

acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, acid citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- Naphthalenesulfonic Acid, 4-Toluenesulfonic Acid, Camphorsulfonic Acid, Glucoheptonic Acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic) Acid, 3-Phenylpropionic Acid, Trimethylacetic Acid, tertiary-Butylacetic Acid, Laurylsulfuric Acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like; either

salts formed when an acidic proton present in the parent compound is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. Pharmaceutically acceptable salts are understood to be non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, Seventeenth Ed., Mack Publishing Company, Easton, PA, 1985.

The compounds of the present disclosure may have asymmetric centers. Compounds of the present disclosure that contain an asymmetrically substituted atom can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of materials. All chiral forms, diastereomeric forms, all mixtures of chiral or diastereomeric forms, and racemic forms are within the scope of this disclosure, unless the specific stereochemistry or isomeric form is specifically indicated. One skilled in the art will also understand that when a compound is referred to as an (R)-stereoisomer, it may contain the corresponding (S)-stereoisomer as an impurity, i.e., the (S)-stereoisomer in less than about 5%, preferably 2% by weight. and then i know indicates as a mixture of R and S isomers, the amounts of R or S isomer in the mixture are greater than about 5%, preferably 2% w/w.

Certain compounds of the present disclosure may exist as tautomers and/or geometric isomers. All possible cis and trans tautomers and isomers, as individual forms and mixtures thereof, are within the scope of this disclosure. Furthermore, as used herein, the term "alkyl" includes all possible isomeric forms of said alkyl group, although only a few examples are set forth. Furthermore, when cyclic groups such as aryl, heteroaryl, heterocyclyl are substituted, they include all positional isomers although only a few examples are set forth. Furthermore, all hydrates of a compound of the present disclosure are within the scope of this disclosure.

"Optional" or "optionally" means that the event or circumstance described below may, but need not, occur, and that the disclosure includes instances in which the event or circumstance occurs and instances in which it does not. For example, "heterocyclyl group optionally substituted with an alkyl group" means that alkyl may, but need not, be present, and the description includes situations where the heterocyclyl group is substituted with an alkyl group and situations where the heterocyclyl group it is not substituted with alkyl.

It should be understood that when the compounds disclosed herein have unfilled valences, then the valences must be filled by hydrogen.

Isotopologists (isotopically labeled analogs) of the compounds described herein are also provided herein. Substitution with isotopes such as deuterium may provide certain therapeutic benefits derived from increased metabolic stability, such as increased in vivo half-life or reduced dosage requirements. In some embodiments, at any position in a compound described herein, or a pharmaceutically acceptable salt thereof, that has a hydrogen, the hydrogen atom may be replaced with hydrogen 2 (deuterium) or hydrogen 3 (tritium).

A "pharmaceutically acceptable carrier or excipient" means a carrier or excipient that is useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic, and is not biologically or otherwise undesirable, and includes a carrier or excipient that is it is acceptable for both veterinary and human pharmaceutical use. "A pharmaceutically acceptable carrier/excipient" as used in the specification and claims includes both one and more than one such excipient.

A "subject" refers to an animal that is the object of treatment, observation, or experiment. "Animal" includes warm and cold blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. "Mammal" includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cattle, horses, primates such as monkeys, chimpanzees, and apes, and, in particular, humans. In some embodiments, the subject may be human. In some embodiments, the subject may be a child and/or an infant, eg, a child or infant with a fever. In other embodiments, the subject can be an adult.

"What is treated" or "treatment" of a disease includes:

(1) prevent disease, that is, cause clinical symptoms of disease not to develop in a mammal that may be exposed or predisposed to disease but is not yet experiencing or showing symptoms of disease;

(2) inhibit the disease, that is, stop or reduce the development of the disease or its clinical symptoms; or (3) alleviate the disease, ie, cause regression of the disease or its clinical symptoms.

A "therapeutically effective amount" means that amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof that, when administered to a subject to treat a disease, is sufficient to effect said treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.

Accomplishments:

In additional embodiments 1-54 below, the present disclosure includes:

1. In embodiment 1, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, are as defined in the Summary.

2. In embodiment 2, the compounds of embodiment 1, or a pharmaceutically acceptable salt thereof, are those in which ring B is phenyl or phenyl substituted with 1, 2, 3 or 4 of Rj, Rk, R1 and Rm where Rj, Rk, R1 and Rm are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl and haloalkoxy. Within embodiment 2, in a group of compounds, or a pharmaceutically acceptable salt thereof, ring B is phenyl substituted with 1, 2, 3 or 4 of Rj, Rk, R1 and Rm where Rj, Rk, R1 and Rm are independently selected from methyl, ethyl, fluoro, chloro, methoxy, trifluoromethyl, and trifluoromethoxy. Within embodiment 2, in another group of compounds, or a pharmaceutically acceptable salt thereof, ring B is phenyl.

3. In embodiment 3, the compounds of embodiment 1, or a pharmaceutically acceptable salt thereof, are those in which ring B is an unsubstituted 5- or 6-membered cycloalkyl or a 5- or 6-membered cycloalkyl substituted with 1,2, 3, or 4 of Rj, Rk, R1 and Rm wherein Rj, Rk, R1 and Rm are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl and haloalkoxy. Within embodiment 3, ring B is cyclopentyl, cyclohexyl, cyclopentyl substituted with 1 or 2 of Rj and Rk where Rj and Rk are independently selected from fluorine, hydroxy and methyl, or cyclohexyl substituted with 1 or 2 of Rj and Rk where Rj, Rk, R1 and Rm are independently selected from fluorine, hydroxy and methyl. Within embodiment 3, in a group of compounds, or a pharmaceutically acceptable salt thereof, ring B is

either

unsubstituted or substituted with 1, 2, 3 or 4 of Rj, Rk, R1 and Rm, where Rj, Rk, R1 and Rm are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl and haloalkoxy. Within embodiment 3, in another group of compounds, or a pharmaceutically acceptable salt thereof, ring B is

either

unsubstituted or substituted with 1 or 2 of Rj and Rk, where Rj and Rk are independently selected from fluorine, hydroxy and methyl. Within embodiment 3, in yet another group of compounds, or a pharmaceutically acceptable salt thereof, ring B is

either

unsubstituted or substituted with one or two methyl groups. Within embodiment 3, in yet another group of compounds, or a pharmaceutically acceptable salt thereof, ring B is:

, preferably,

either

4. In embodiment 4, the compounds of embodiment 1, or a pharmaceutically acceptable salt thereof, are those in which ring B is an unsubstituted 5-, 6-, or 7-membered saturated heterocyclyl or a 5, 6 or 7 members substituted with 1, 2, 3 or 4 of Rj, Rk, R' and Rm wherein Rj, Rk, R' and Rm are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl and haloalkoxy. Within embodiment 4 in yet another group of compounds, or a pharmaceutically acceptable salt thereof, ring B is:

each ring is unsubstituted or substituted with 1,2, 3 or 4 of Rj, Rk, R' and Rm, where Rj, Rk, R' and Rm are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl and haloalkoxy. Within embodiment 4, in another group of compounds, or a pharmaceutically acceptable salt thereof, the ring

each ring is unsubstituted or substituted with 1 or 2 of Rj and Rk, where Rj and Rk are independently selected from fluorine, chlorine, hydroxy and methyl. Within embodiment 4, in yet another group of compounds or a pharmaceutically acceptable salt thereof, ring B is:

each ring is unsubstituted or substituted with one or two methyl groups. Within embodiment 4, in yet another group of compounds, or a pharmaceutically acceptable salt thereof, ring B is:

each ring is unsubstituted or substituted with one to four methyl groups. Within embodiment 4, in yet another group of compounds, or a pharmaceutically acceptable salt thereof, ring B is:

5. In embodiment 5, the compounds of embodiment 1, or a pharmaceutically acceptable salt thereof, are those in which ring B is a spirocycloalkyl or a spiroheterocycloamino, in which each of the rings is unsubstituted or is substituted with 1, 2, 3 or 4 of Rj, Rk, R' and Rm wherein Rj, Rk, R' and Rm are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl and haloalkoxy. Within embodiment 5, in a group of compounds, or a pharmaceutically acceptable salt thereof, are those in which ring B is a spirocycloalkyl in which each of the rings is unsubstituted or substituted with 1,2, 3 or 4 of Rj, Rk, R, and Rm wherein Rj, Rk, R and Rm are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl and haloalkoxy. Within embodiment 5, in a group of compounds, or a pharmaceutically acceptable salt thereof, ring B is:

each ring is unsubstituted or substituted with 1,2, 3 or 4 of Rj, Rk, R' and Rm, where Rj, Rk, R' and Rm are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl and haloalkoxy. Within embodiment 5, in a group of compounds, or a pharmaceutically acceptable salt thereof, are those in which ring B is a spiroheterocycloamino, in which each of the rings is unsubstituted or substituted with 1,2 , 3 or 4 of Rj, Rk, R' and Rm wherein Rj, Rk, R' and Rm are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl and haloalkoxy.

6. In embodiment 6, the compounds of any of embodiments 1 to 5 and the groups contained therein, or a pharmaceutically acceptable salt thereof, are those in which Z1 and Z2 are independently C or CH. Within the groups of compounds of embodiment 6 in a group of compounds, or a pharmaceutically acceptable salt thereof, Z1 and Z2 are each CH. Within the groups of compounds of embodiment 6, or a pharmaceutically acceptable salt thereof, in another group of compounds, Z1 and Z2 are each CH and -alk-R1 is attached to carbon (a) in Formula (I) . Within the groups of compounds of embodiment 6, or a pharmaceutically acceptable salt thereof, in yet another group of compounds Z1 and Z2 are each CH and -alk-R1 attached to carbon (a) and R2 is attached to carbon (b ) in Formula (I).

7. In embodiment 7, the compounds of any of embodiments 1 to 5 and the groups contained therein, or a pharmaceutically acceptable salt thereof, are those in which one of Z1 and Z2 is N and the other is C or CH. In embodiment 7, in another group of compounds, the compounds of any one of embodiments 1 to 5 and the groups contained therein, or a pharmaceutically acceptable salt thereof, are those in which Z1 and Z2 are each N( nitrogen). Within the groups of compounds of embodiment 7, or a pharmaceutically acceptable salt thereof, in another group of compounds, -alk-R1 is attached to carbon (a) in Formula (I). Within the groups of compounds of embodiment 7, or a pharmaceutically acceptable salt thereof, in another group of compounds or a pharmaceutically acceptable salt thereof, -alk-R1 is attached to carbon (a), and R2 is attached to carbon (b) in Formula (I).

8. In embodiment 8, the compounds of any of embodiments 1 to 7 and the groups contained therein, or a pharmaceutically acceptable salt thereof, are those in which alk in -(alk)-R1 is -(CH2 )2-*,-( CH2)3-*, -(CH2)4-*, -CH2CH(CH3)CH2-*, -O-(CH2)2-*, or -O-(CH2)3-* , preferably alk is -O-(CH2)3-*, where * indicates the point of attachment to -Rl. Within embodiment 8, in a group of compounds, or a pharmaceutically acceptable salt thereof, Rl is -NR6R7 where -NR6R7 is amino, methylamino, ethylamino, dimethylamino, or diethylamino. Within embodiment 8, or a pharmaceutically acceptable salt thereof, R1 is unsubstituted heterocyclyl. Within embodiment 8, or a pharmaceutically acceptable salt thereof, in another group of compounds, or a pharmaceutically acceptable salt thereof, Rl is heterocyclyl substituted with 1,2 or 3 of Ra, Rb and Rc, where Ra, Rb and Rc are independently selected from alkyl, hydroxy, alkoxy, and halo. Preferably, R1 is a saturated heterocyclyl such as azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, or tetrahydrofuranyl, and each heterocyclyl is unsubstituted or substituted. with 1 or 2 of Ra and Rb wherein Ra and Rb are independently selected from methyl, hydroxy, methoxy and fluorine. Within embodiment 8, in another group of compounds, or a pharmaceutically acceptable salt thereof, -alk-R1 is -O-(CH2)3-pyrrolidin-1-yl, -O-(CH2)3-piperidin-1 -yl, or -O-(CH2)3-morpholin-4-yl where the pyrrolidin-1-yl, piperidin-1-yl, and morpholin-4-yl of -O-(CH2)3-pyrrolidin-1 -yl, -O-(CH2)3-piperidin-1-yl, and -O-(CH2)3-morpholin-4-yl are unsubstituted or substituted with 1 or 2 of Ra and Rb, where Ra and Rb are independently selected from methyl, hydroxy, methoxy and fluorine. Within embodiment 8, in yet another group of compounds, or a pharmaceutically acceptable salt thereof, -alk-Rl is -O-(CH2)3-Rl wherein Rl is pyrrolidin-1-yl, 3-hydroxy-3-methylpyrrolidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl, 3-fluoroazetidinyl, 3-fluoropyrrolidinyl, 3(R)-fluoropyrrolidinyl, 3(S )-fluoropyrrolidinyl or 3,3-dimethylpyrrodin-1-yl, preferably pyrrolidin-1-yl. In embodiment 8, the compounds of any one of embodiments 1 to 7 and the groups contained therein, or a pharmaceutically acceptable salt thereof, are those in which -alk-Rl is -O-(CH2)-Rl wherein Rl is 1-methylpyrrolidin-3-yl or 1-methylpiperidin-3-yl.

9. In embodiment 9, the compounds of any of embodiments 1 to 8 and the groups contained therein, or a pharmaceutically acceptable salt thereof, are those in which R2 is alkyl, halo, hydroxy, or alkoxy. Within embodiment 9, in a group of compounds, or a pharmaceutically acceptable salt thereof, R2 is alkyl, halo, or alkoxy. Within embodiment 9, in another group of compounds, or a pharmaceutically acceptable salt thereof, R2 is alkoxy, preferably methoxy or ethoxy. Within embodiment 9, in a group of compounds, or a pharmaceutically acceptable salt thereof, R2 is halo, preferably chlorine or fluorine. Within embodiment 9, in a group of compounds, or a pharmaceutically acceptable salt thereof, R2 is alkyl, preferably methyl or ethyl. 10. In embodiment 10. the compounds of any of embodiments 1 to 9 and the groups contained therein, or a pharmaceutically acceptable salt thereof, are those in which R4 is alkyl, preferably methyl or isopropyl.

11. In embodiment 11, the compounds of any one of embodiments 1 to 9 and the groups contained therein, or a pharmaceutically acceptable salt thereof, are those in which R4 is NReRf (where Re is hydrogen or alkyl, and Rf is hydrogen, alkyl, deuterated alkyl, alkylthioalkyl, acyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cyanoalkyl, carboxyalkyl, alkoxycarbonylalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl) where cycloalkyl, aryl , heteroaryl and heterocyclyl either alone or as part of cycloalkylalkyl, aralkyl, heteroaralkyl and heterocyclylalkyl at Rf is unsubstituted or substituted with 1, 2 or 3 of Rg, Rh and Ri where Rg, Rh and Ri are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, cyano, carboxy, alkoxycarbonyl, and haloalkoxy. Within embodiment 11, in a group of compounds, or a pharmaceutically acceptable salt thereof, R4 is NReRf (where Re is hydrogen or alkyl, and Rf is alkyl, cyanoalkyl, carboxyalkyl, alkoxycarbonylalkyl, deuterated alkyl, alkylthioalkyl, hydroxyalkyl , cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl) wherein cycloalkyl, aryl, heteroaryl, and heterocyclyl alone or as part of cycloalkylalkyl, aralkyl, heteroaralkyl, and heterocyclylalkyl at Rf are not substituted or are substituted with 1, 2 or 3 of Rg, Rh and Ri where Rg, Rh and Ri are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, cyano, carboxy, alkoxycarbonyl and haloalkoxy. Within embodiment 11, in another group of compounds, or a pharmaceutically acceptable salt thereof, R4 is -NRe-alkyl, preferably R4 is -NH-alkyl or -N(alkyl)-alkyl, preferably R4 is -NH-methyl , -NH-ethyl, -NH-n-propyl, -NH-isopropyl, -N(methyl)(isopropyl), -NH-n-butyl, -NH-isobutyl, -NH-tert-butyl, -NH-* CH(CH3)CH2CH3 (wherein *C is (R) or (s)), or NH-pentyl (all isomers) more preferably -NH-methyl, -NH-ethyl, -NH-n-propyl or - NH-isopropyl. Within embodiment 11, in another group of compounds, or a pharmaceutically acceptable salt thereof, R4 is -NRe-cyanoalkyl, preferably R4 is -NH-(CH2)2-CN or -NH-(CH2)3-CN. Within embodiment 11, in another group of compounds, or a pharmaceutically acceptable salt thereof, R4 is -NRe-carboxyalkyl, preferably R4 is -NH-(CH)-C(=O)OH. Within embodiment 11, in another group of compounds, or a pharmaceutically acceptable salt thereof, R4 is -NRealkoxycarbonylalkyl, preferably R4 is -NH-(CH)-C(=O)-(CH2)-CH3. Within embodiment 11, in another group of compounds, or a pharmaceutically acceptable salt thereof, R4 is -NRe-(deuterated alkyl), preferably R4 is -NH-CD(CH3)2 (wherein D is deuterium). Within embodiment 11, in another group of compounds, or a pharmaceutically acceptable salt thereof, R4 is -NRe-alkylthioalkyl, preferably R4 is -NH-(CH2)2-S-CH3. Within embodiment 11, in another group of compounds, or a pharmaceutically acceptable salt thereof, R4 is -NRe-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with one or two of Rg or Rh, wherein Rg and Rh are independently selected from alkyl, hydroxy, alkoxy, cyano, carboxy, carboxycarbonyl, halo, haloalkyl and haloalkoxy, preferably R4 is -NH-cyclopropyl, -NH(1-methylcyclopropyl), -NH(1-cyanocyclopropyl), - NH(2-cyanocyclopropyl), -NH(1-carboxycyclopropyl), -NH(1-[ethoxycarbonyl]cyclopropyl), -NH-cyclobutyl, -NH(3-hydroxycyclobutyl), -NH-cyclopentyl, -N(methyl)( cyclopentyl), -NH-cyclohexyl, -NH-(3-fluorocyclobutyl), -NH-(3,3-difluorocyclobutyl) or -NH-(3,3-dimethylcyclobutyl), more preferably -NH-cyclopropyl, NH-cyclopentyl or NH-cyclohexyl. Within embodiment 11, in another group of compounds or a pharmaceutically acceptable salt thereof, R4 is:

Within embodiment 11, in another group of compounds, or a pharmaceutically acceptable salt thereof, R4 is -NH-heterocyclyl, wherein heterocyclyl is unsubstituted or substituted with 1,2 or 3 of Rg, Rh and Ri wherein Rg, Rh, and Ri are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, and haloalkoxy, preferably R4 is -NH-piperidin-4-yl, -NH-tetrahydropyran-4-yl, -NH-oxetan -3-yl, -NH-tetrahydrofuran-3-yl, -NH-(2,6-dimethyltetrahydropyran-4-yl) or -NH-(1-alkylpiperidin-4-yl). Within embodiment 11, in another group of compounds, or a pharmaceutically acceptable salt thereof, R4 is -NH-cycloalkylalkyl, wherein the cycloalkyl of the cycloalkylalkyl is unsubstituted or substituted with 1 or 2 of Rg and Rh, in wherein Rg and Rh are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl and haloalkoxy, preferably R4 is -NH-CH2-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 or 2 of Rg and Rh wherein Rg and Rh are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, and haloalkoxy, more preferably R4 is -NH-CH2-cyclopropyl, -NH-*CH(CH3)cyclopropyl (wherein *C is ( R) or (S)), -NH-C^-cyclobutyl, -NH-*CH(CH3)cyclobutyl where *C is (R) or (S), -NH-CH2-cyclopentyl, -NH-CH2 -cyclohexyl, -NH-CH ² -(3-fluorocyclobutyl), -NH-CH ² -(3,3-difluorocyclobutyl), -NH-CH2-(3,3-dimethylcyclobutyl), -NH-CH2-(1- methylcyclopropyl), -NH-CH ² -(1-methylcyclobutyl),-NH-(CH2)2-ci chloropropyl, -NH-(CH2)2-cyclopentyl or NH-(CH2)2-cyclohexyl, even more preferably -NH-CH2-cyclopropyl or NH-CH2-cyclobutyl. Within embodiment 11, in another group of compounds, or a pharmaceutically acceptable salt thereof, R4 is -NH-(hydroxyalkyl) or -NH-(alkoxyalkyl), preferably R4 is -NH-(2-hydroxyethyl), -NH -(2-hydroxybutyl), -NH-(2-hydroxy-2-methylbutyl), -NH-(2-hydroxy-2-methylpropyl), -NH-(2-methoxyethyl), -NH-(2-methoxypropyl) , -NH-(2-methoxy-2-methylpropyl) or -NH-(2-methoxybutyl). Within embodiment 11, in another group of compounds, or a pharmaceutically acceptable salt thereof, R4 is -NH-heterocyclylalkyl, wherein the heterocyclyl of heterocyclylalkyl is unsubstituted or substituted with 1, 2 or 3 of Rg, Rh and Ri where Rg, Rh and Ri are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl and haloalkoxy, preferably R4 is -NH-CH ² -oxetan-3-yl, -NH-CH2-piperidin-4- yl, -NH-CH2-tetrahydropyran-4-yl, -NH-CH2-tetrahydrofuran-3-yl, -NH-CH2-(1-alkylpiperidin-4-yl), -NH-(CH2)2-oxetan-3 -yl, -NH-(CH2)2-piperidin-4-yl, -NH-(CH2)2-tetrahydropyran-4-yl, -NH-(CH2)2-tetrahydrofuran-3-yl or -NH-(CH2 )2-(1-alkylpiperidin-4-yl). Within embodiment 11, in another group of compounds, or a pharmaceutically acceptable salt thereof, R4 is -NH-haloalkyl, preferably R4 is -NH-2-fluoroethyl, -NH-2,2-difluoroethyl, -NH-( 2,2,2-trifluoroethyl), -NH-(3-fluoropropyl), -NH-(3,3-difluoropropyl) or -NH-(3,3,3-trifluoropropyl). Within embodiment 11, in another group of compounds, or a pharmaceutically acceptable salt thereof, R4 is -NH-heteroaralkyl unsubstituted or substituted with 1 or 2 of Rg and Rh, wherein Rg and Rh are independently selected from alkyl , hydroxy, alkoxy, halo, haloalkyl and haloalkoxy. Within embodiment 11, in another group of compounds, or a pharmaceutically acceptable salt thereof, R4 is -NH-aralkyl unsubstituted or substituted with 1 or 2 of Rg and Rh, wherein Rg and Rh are independently selected from alkyl , hydroxy, alkoxy, halo, haloalkyl and haloalkoxy, preferably R4 is -NH-(2-phenethyl), -NH-benzyl or -NH-(2,4-dimethoxybenzyl). Within embodiment 11, in another group of compounds, or a pharmaceutically acceptable salt thereof, R4 is -NH-methyl, -NH-ethyl, -NH-n-propyl, -NH-isopropyl, -N(methyl)( isopropyl), -NH-n-butyl, -NH-isobutyl, -NH-tert-butyl, NH-pentyl (all isomers), -NH-cyclopropyl, -NH-cyclobutyl, -NH(3-hydroxycyclobutyl), - NH-cyclopentyl, -N(methyl)(cyclopentyl), -NH-cyclohexyl, -NH-(3-fluorocyclobutyl), -NH-(3,3-difluorocyclobutyl), -NH-(3,3-dimethylcyclobutyl), - NH-piperidin-4-yl, -NH-tetrahydropyran-4-yl, -NH-oxetan-3-yl, -NH-tetrahydrofuran-3-yl, -NH-(2,6-dimethyltetrahydropyran-4-yl), -NH-(1 -alkylpiperidin-4-yl), -NH-CH2-cyclopropyl, -NH-CH2-cyclobutyl, -NH-CH2-cyclopentyl, -NH-CH2-cyclohexyl, -NH-CH2-(3-fluorocyclobutyl ), -NH-CH2-(3,3-difluorocyclobutyl), -NH-CH2-(3,3-dimethylcyclobutyl), -NH-CH2-(1-methylcyclopropyl), -NH-CH2-(1-methylcyclobutyl), -NH-(CH2)2-cyclopropyl, -NH-(CH2)2-cyclopentyl, NH-(CH2)2-cyclohexyl, -NH-(2-hydroxyethyl), -NH-(2-hydroxy ibutyl), -NH-(2-hydroxy-2-methylbutyl), -NH-(2-methoxyethyl), -NH-(2-methoxy-2-methylbutyl), -NH-(2-methoxybutyl), -NH- 2-fluoroethyl, -NH-2,2-difluoroethyl, -Nh -(2,2,2-trifluoroethyl), -NH-(3-fluoropropyl), -NH-(3,3-difluoropropyl), -NH-( 3,3,3-trifluoropropyl), -NH(2-phenethyl), -NH(2-phenethyl), pyrrolidin-1-yl, cyclopropyl, cyclobutyl or cyclopentyl.

12. In embodiment 12, the compounds of any one of embodiments 1 to 11 and the groups contained therein, or a pharmaceutically acceptable salt thereof, are those in which R3 is hydrogen, chlorine or -NH-isopropyl.

13. In embodiment 13, the compounds of any of embodiments 1 to 12 and the groups contained therein, or a pharmaceutically acceptable salt thereof, are those in which X is carbon or nitrogen. Within embodiment 13, in a group of compounds, or a pharmaceutically acceptable salt thereof, wherein X is carbon. Within embodiment 13, in a group of compounds, or a pharmaceutically acceptable salt thereof, wherein X is nitrogen.

14. In some embodiments, the compounds of embodiment 1, or a pharmaceutically acceptable salt thereof, have the structure of Formula (Ia), or a pharmaceutically acceptable salt thereof:

in which: n is 1, 2 or 3; and R1, R2, R3, and R4 are as defined herein, for example, in embodiment 1. Within embodiment 14, alk is -OCH2CH2CH2-*, where * indicates the point of attachment to R1. Within embodiment 14, R1 is heterocyclyl, preferably a 5-membered nitrogen-containing heterocyclyl (eg, pyrrolidine).

Within embodiment 14, R2 is unsubstituted C i-4 alkoxy, preferably methoxy. Within embodiment 14, R3 is H. Within embodiment 14, formula (la), or a pharmaceutically acceptable salt thereof, has the structure of formula (Ic), or a pharmaceutically acceptable salt thereof:

15. In some embodiments, the compounds of embodiment 1, or a pharmaceutically acceptable salt thereof, have the structure of Formula (Ib), or a pharmaceutically acceptable salt thereof:

Where R1, R2, R3, Re, Rf, and ring B are as defined herein, for example, in embodiment 1. Within embodiment 15, alk is -OCH2CH2CH2-*, where * indicates the point of attachment to R1. Within embodiment 15, R1 is heterocyclyl, preferably a 5-membered saturated nitrogen-containing heterocyclyl (eg, pyrrolidinyl). Within embodiment 15, R2 is unsubstituted C1-4 alkoxy, preferably methoxy. Within embodiment 15, R3 is H. Within embodiment 15, ring B is a 5-, 6-, or 7-membered nitrogen-containing heterocyclyl that is optionally substituted. Within embodiment 15, ring B is a 5-, 6-, or 7-membered nitrogen-containing heterocyclyl substituted with 1 to 4 substituents independently selected from alkyl

C1-4, preferably methyl. Within embodiment 15, Formula (la), or a pharmaceutically acceptable salt thereof, has the structure of Formula (Id), or a pharmaceutically acceptable salt thereof:

Within embodiment 15 and formula (Id), or a pharmaceutically acceptable salt thereof, alk is -OCH2CH2CH2-*, where * indicates the point of attachment to R1; R1 is heterocyclyl, preferably a 5-membered saturated nitrogen-containing heterocyclyl (eg pyrrolidine); R2 is unsubstituted C-m alkoxy, preferably methoxy; R3 is H;

and ring B is a 5-, 6- or 7-membered nitrogen-containing heterocyclyl which is optionally substituted. Within embodiment 15 and Formula (Id), or a pharmaceutically acceptable salt thereof, Re is H or methyl, preferably H. Within embodiment 15 and Formula (Id), or a pharmaceutically acceptable salt thereof, Rf is H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, or heterocyclyl, wherein cycloalkyl, cycloalkylalkyl, aralkyl, and heterocyclyl are unsubstituted or substituted with one or two methyl or hydroxy. Preferably Rf is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl and cyclohexyl.

16. In embodiment 16, the compounds of embodiment 1, or a pharmaceutically acceptable salt thereof, are those in which the compound, or a pharmaceutically acceptable salt thereof, is selected from compound numbers: 1,2, 3 , 4, 5, 6 , 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20. 22, 23, 24, 25, 26, 27, 28, 29, 30 .

31.33, 34, 39, 41,42, 43, 44, 45, 46, 47, 48, 49, 50, 51,53, 54, 55, 57, 58, 59, 60, 61,62, 63, 64, 65, 66, 67, 68, 69, 71.72, 73, 74, 77, 78, 81,82, 84, 85, 86, 87, 88, 89, 91,92, 93, 94, 95, 96, 97, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 112, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 134, 135, 136, 137, 138, 139, 140, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 167, 168, 169, 170. 171 172173 174

175 176 177178 179180181 182183184185 186 187188189190 191 192193 194 and 195 as shown in Table 1 or Table 2, or a parent compound of the salt as shown in Table 1 or Table 2, or a pharmaceutically acceptable salt of the compound original.

17. In embodiment 17, the compounds of embodiment 1, or a pharmaceutically acceptable salt thereof, are those in which the compound, or a pharmaceutically acceptable salt thereof, is selected from compound numbers: 1,2, 3 , 4, 5, 6 , 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20. 22, 23, 24, 25, 26, 27, 28, 29, 30 .

31.33, 34, 39, 41,42, 43, 44, 45, 46, 47, 48, 49, 50, 51,53, 54, 55, 57, 58, 59, 60, 61,62, 63, 64, 65, 66, 67, 68, 69, 71.72, 73, 74, 77, 78, 81,82, 84, 85, 86, 87, 88, 89, 91,92, 93, 94, 95, 96, 97, 99, 100. 101,102, 103, 104, 105, 106, 107, 108, 112, 115, 116, 117, 118, 119, 120. 121, 122, 123, 124, 125 and 126, as shown in Table 1, or a salt parent compound as shown in Table 1, or a pharmaceutically acceptable salt of the parent compound.

18. In embodiment 18, the compounds of embodiment 1, or a pharmaceutically acceptable salt thereof, are those in which the compound, or a pharmaceutically acceptable salt thereof, is selected from compound numbers: 134, 135, 136 , 137, 138, 139, 140. 149, 150. 151, 152, 153, 154, 155, 156, 157, 158, 159, 160.

161, 162, 163, 164, 165, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194 and 195 as shown in Table 2, or a salt parent compound as shown in Table 2, or a pharmaceutically acceptable salt of the parent compound.

19. Embodiment 19 provides a pharmaceutical composition comprising a compound of any one of embodiments 1 to 18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

20. Embodiment 20 provides a compound of embodiments 1 to 18, or a pharmaceutically acceptable salt thereof, for use in a method of inhibiting G9a.

21. In embodiment 21, the cell of embodiment 20 may be a cancer cell.

22. Embodiment 22 provides a compound of embodiments 1 to 18, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 19, for use in a method of ameliorating and/or treating a hemoglobinopathy.

23. In embodiment 23, the hemoglobinopathy of embodiment 22 may be sickle cell disease or beta-thalassemia.

24. Embodiment 24 provides a compound of embodiments 1 to 18, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 19, for use in a method of ameliorating and/or treating cancer.

25. In embodiment 25, the cancer of embodiment 24 may be selected from: colorectal cancer, osteosarcoma cancer, acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); adrenocortical carcinoma, Kaposi's sarcoma (soft tissue sarcoma); an AIDS-related lymphoma (lymphoma); a primary CNS lymphoma; an anal cancer; a gastrointestinal carcinoid tumor; an astrocytoma; an atypical teratoid/rhabdoid tumor; a basal cell carcinoma of the skin; a cancer of the bile ducts; bladder cancer; a bone cancer (includes Ewing's sarcoma and osteosarcoma and malignant fibrous histiocytoma); a brain tumor; a breast cancer; a bronchial tumor, a Burkitt's lymphoma; a heart tumor; an embryonal tumor (brain cancer); a germ cell tumor (brain cancer); a primary CNS lymphoma; cervical cancer; a cholangiocarcinoma; a chordoma; a chronic lymphocytic leukemia (CLL); a chronic myelogenous leukemia (CML); a chronic myeloproliferative neoplasm; colorectal cancer; a craniopharyngioma (brain cancer); a cutaneous T-cell lymphoma; a ductal carcinoma in situ (DCIS); endometrial cancer (uterine cancer); an ependymoma (brain cancer); an esophageal cancer; an esthesioneuroblastoma; Ewing's sarcoma (bone cancer); extracranial germ cell tumor; extragonadal germ cell tumor; eye cancer; intraocular melanoma; a retinoblastoma; fallopian tube cancer; a fibrous histiocytoma of bone; gallbladder cancer; a gastric (stomach) gastrointestinal stromal tumor (GIST) (soft tissue sarcoma); a CNS germ cell tumor (brain cancer); an extracranial germ cell tumor; an extragonadal germ cell tumor; an ovarian germ cell tumor; testicular cancer; gestational trophoblastic disease; a hairy cell leukemia; head and neck cancer; hepatocellular (liver) cancer; a histiocytosis, a Langerhans cell; Hodgkin's lymphoma; hypopharyngeal cancer (cancer of the head and neck); an intraocular melanoma; an islet cell tumor; a pancreatic neuroendocrine tumor; kidney (renal cell) cancer; a Langerhans cell histiocytosis; cancer of the larynx (cancer of the head and neck); a leukemia; a cancer of the lip and oral cavity (cancer of the head and neck); lung cancer (non-small cell and small cell); a lymphoma; a male breast cancer; a melanoma; a Merkel cell carcinoma (skin cancer); to mesothelioma; a malignant mesothelioma; metastatic squamous cell carcinoma of the neck with an occult primary (head and neck cancer); a midline tract carcinoma involving the NUT gene; mouth cancer (cancer of the head and neck); multiple syndromes of endocrine neoplasia; multiple myeloma/plasma cell neoplasms; a mycosis fungoides (lymphoma); a myelodysplastic syndrome, a myelodysplastic/myeloproliferative neoplasm; a cancer of the nasal cavity and paranasal sinus (cancer of the head and neck); a cancer of the nasopharynx (cancer of the head and neck); a nasopharyngeal cancer - neuroblastoma; a non-Hodgkin's lymphoma; an oral cancer; lip and oral cavity cancer and oropharyngeal cancer (cancer of the head and neck); ovarian cancer; pancreatic cancer; a papillomatosis; a paraganglioma; a cancer of the paranasal sinus and nasal cavity (cancer of the head and neck); parathyroid cancer; penile cancer; to pharyngeal cancer (cancer of the head and neck); a pheochromocytoma; a pituitary tumor; a pleuropulmonary blastoma; a primary CNS lymphoma; a primary peritoneal cancer; prostate cancer; a rectal cancer; a rhabdomyosarcoma (soft tissue sarcoma); salivary gland cancer (head and neck cancer); a salivary gland tumor; a vascular tumor (soft tissue sarcoma); a uterine sarcoma; a Sezary syndrome (lymphoma); small intestine cancer; a squamous cell carcinoma; a skin cancer; a squamous cell cancer of the neck with an occult primary, metastatic (cancer of the head and neck); a cutaneous T-cell lymphoma; throat cancer (head and neck cancer); a nasopharyngeal cancer; an oropharyngeal cancer; hypopharyngeal cancer; a thymoma and a thymic carcinoma; to thyroid cancer; urethral cancer; a vaginal cancer; a vascular tumor (soft tissue sarcoma); vulvar cancer; a myelodysplastic syndrome (MDS); and a Wilms tumor.

26. In embodiment 26, the cancer of any one of embodiments 24 to 25 may be selected from: a myelodysplastic syndrome (MDS); acute myeloid leukemia (AML); ovarian cancer; colon cancer; and non-small cell lung cancer (NSCLC).

27. Embodiment 27 provides a compound of embodiments 1 to 18, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 19, for use in a method of ameliorating and/or treating an autoimmune or inflammatory disease.

28. In embodiment 28, the autoimmune or inflammatory disease of embodiment 27 can be selected from: arthritis, atherosclerosis, multiple sclerosis, myasthenia gravis, Crohn's disease, graft-versus-host disease, psoriasis, granulomatous colitis, lymphocyte colitis, collagenous colitis, ulcerative colitis, celiac disease, subepidermal bullous disorders, systemic lupus erythematosus, discoid lupus erythematosus, cutaneous lupus, dermatomyositis, polymyositis, Sjogren's syndrome, primary biliary cirrhosis, chronic active hepatitis, chronic fatigue syndrome, and vasculitis.

29. In embodiment 29, the autoimmune or inflammatory disease of any of embodiments 27 to 28 may be Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, primary biliary cirrhosis, and graft versus host disease.

Representative compounds of Formula (I), or their salts, are disclosed in Tables 1 and 2 below. Although Tables 1 and 2 may show a specific salt of a compound of Formula (I), those skilled in the art will be able to recognize the parent compound (wherein "parent compound" is a compound without a salt moiety present), and other salts, such as pharmaceutically acceptable salts, of those compounds in Tables 1 and 2.

Table 1

[Table 2]

General synthesis scheme

The compounds of this disclosure can be prepared by the methods described in the reaction schemes shown below.

Starting materials and reagents used in the preparation of these compounds are available from commercial suppliers such as Sigma-Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or are prepared by methods known to those skilled in the art following the procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd' Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this disclosure may be synthesized, and various modifications to these schemes may be made and would be suggested to one of ordinary skill in the art reading this disclosure. Starting materials, intermediates, and final products of the reaction(s) may be isolated and purified if desired using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

Unless otherwise specified, the reactions described herein take place at atmospheric pressure in a temperature range of from about -78°C to about 150°C, such as from about 0°C to about 125°C and further such as about room (or ambient) temperature, eg, about 20°C. The routes shown and described herein are illustrative only and are not intended to limit the scope of the claims in any way, nor should they be construed as such. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and devise alternative routes based on the disclosures in this document; all such modifications and alternate routes are within the scope of the claims.

Compounds of Formula (I) in which ring B is saturated 5-, 6-, or 7-membered cycloalkyl or heterocyclyl, Z1 and Z2 are independently selected from CH or C (where one substituent is attached), X is C, and R1, R2, R3 and R4 are as defined in the Summary, can be prepared by the following procedure described in Scheme 1 below.

The reaction of a compound of formula 1 in which -alk-R1, R2 and R3 are as defined in the Summary, or a parent group thereof with 2-oxocycloalkylcarboxylate or 2-oxoheterocyclylcarboxylate of formula 2 in which R is alkyl and ring B is unsubstituted or is substituted with Rj, Rk, Rl and/or Rm as defined in the Summary, in the presence of a catalytic amount of an acid, such as p-toluenesulfonic acid, followed by treatment of the product compound The resulting intermediate with polyphosphoric acid at 90°C to reflux provides a tricyclic ring compound of Formula (I) where R4 is hydroxy. Compounds of formula 1 can be prepared from commercially available materials such as 2-methoxy-5-nitrophenol by methods well known in the art (see references in synthetic examples below). Compounds of formula 2 such as methyl 2-oxocyclopentane-1-carboxylate, methyl 2-oxocyclohexane-1-carboxylate, methyl 4-oxotetrahydrofuran-3-carboxylate and methyl 1-methyl-4-oxopiperidine-3-carboxylate are commercially available. Other compounds of formula 2 are readily available through synthetic procedures well known to those of skill in the art (eg, methyl 4,4-dimethyl-2-oxocyclopentane-1-carboxylate and close analogs, see Gellman et al, Organic Letters, 2004, Vol 6, No. 24, pages 4411-4414). The compound of Formula (I) in which R4 is hydroxy can be converted to other compounds of Formula (I) by first converting it to a corresponding compound in which R4 is halo, eg chloro, followed by other transformations. The reaction conditions used for these transformations depend on the nature of the R4 groups. For example, compounds of Formula (I) where R4 is NReRf (where Re and Rf are as defined in the Summary) can be prepared by reacting the corresponding compound where R4 is halo, such as chlorine, with an amine of formula NHReRf under Buchwald coupling reaction conditions. Compounds of Formula (I) in which R4 is alkyl, cycloalkyl, -cycloalkenyl, heterocyclyl, phenyl or heteroaryl, can be prepared by reacting the corresponding compound in which R4 is chloro with boronic reagents under Suzuki coupling reaction conditions , Zn reagent under Negishi coupling, or tin derivatives under Stille coupling reaction conditions. One skilled in the art will recognize that the R1, R2 and R3 groups may be modified, as necessary, during the above synthetic route.

Alternatively, compounds of formula (I) wherein Z1 and Z2 are independently selected from CH or C (wherein one substituent is attached), X is C and ring B, r1, R2, R3 and R4 are as are defined in the Summary, they can be prepared by the following procedure described in Scheme 2 below.

Scheme 2

Compounds of Formula (I) may also be prepared following the synthetic routes depicted in Scheme 2. Coupling reaction of the compound of formula 3 wherein -alk-R1, R2 and R3 are as defined in the Summary or a parent group thereof, with a compound of formula 4 (wherein ring C is phenyl, 5- or 6-membered heteroaryl, 5- or 6-membered cycloalkenyl, or 5-, 6-, or 7-membered heterocycloalkenyl, each ring mentioned above substituted with Rj Rk, Rl and/or Rm as defined in the Summary, W is -B(OH)2, 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl-, tributylstannil or others appropriate functional groups and R' is H or alkyl) in the presence of appropriate catalysts such as tetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) yields an intermediate of Formula 5. The compound of formula 3 such as 1-[3-(4-bromo-2-methoxy-5-nitrophenoxy)propyl]pyrrolidine can be made from material as commercially available, such as 4-bromo-2-methoxyphenol, via methods well known to those skilled in the art (see synthetic examples below for reference). Compounds of Formula 4 are available from commercial sources. Alternatively, compound 4 where W is 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl or 1,1,1-tributylstannane can be prepared from compound of formula 7 (where M is halo and R' is as defined above) by reacting compound 7 with appropriate reagents such as 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi( 1,3,2-dioxaborolane) or 1,1,1,2,2,2-hexabutyldistanane in the presence of a suitable catalyst such as tetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene ]-dichloropalladium(II), respectively. Compound 4 where W is 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl can undergo hydrolysis to produce the corresponding compound of formula 4 where W is -B(OH)2. Compounds of formula 7 in which M is Br or Cl, such as ethyl 4-chlorothiazole-5-carboxylate, methyl 2-bromobenzoate, methyl 4-chloro-1H-imidazole-5-carboxylate, Methyl 2-chloronicotinate, methyl 3-chloropyrazine-2-carboxylate, methyl 4-chloropyrimidine-5-carboxylate, ethyl 5-chloro-1H-pyrazole-4-carboxylate, 3-bromothiophene-2-carboxylic acid or 2- bromo-3-thiophenecarboxylic acid are commercially available. Compound 7 in which M is -OTf can be prepared from the corresponding commercially available 2-oxocycloalkylcarboxylate or 2-oxoheterocyclocarboxylate starting material, such as 1-tert- 3-methyl 4-oxopiperidine-1,3-dicarboxylate. butyl, by methods well known to those of skill in the art (see Organic Letters, 2012, 14(12):2940-2943; and Organic Letters, 2003, 5(1):59-61).

Alternatively, the compound of formula 5 can be prepared by reacting an organoborane compound of formula 6 with a compound of formula 7 under the coupling conditions described above. The compound of formula (I) is prepared from compound 5 by reduction of the nitro group under suitable reducing conditions, such as treatment with Zn, Fe, tin(II) chloride, or under hydrogenation conditions, such as Pd/ C under hydrogen atmosphere, followed by hydrolysis of the ester group (where R' = -alkyl) under basic reaction conditions (eg, sodium hydroxide (NaOH) or lithium hydroxide (LiOH)) to provide an amino compound of formula 8. The intramolecular amide coupling reaction of compound 8 facilitated by amide coupling reagents well known to those skilled in the art, such as 1-[bis(dimethylamino)-methylene]-1H-3-oxide hexafluorophosphate 1,2,3-triazolo[4,5-b]pyridinium (HATU) and hydroxybenzotriazole (HOBt), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and HOBt, or benzotriazol-1-yl hexafluorophosphate -oxytripyrrolidino-phosphonium (PyBOP) in a suitable solvent, such as dimethylformamide (DMF) or 1,4-dioxane, at room temperature provides a compound of Formula (I) where R4 is hydroxy which can be converted to another compound of Formula (I) as described above in Scheme 1.

Alternatively, compounds of Formula (I) wherein Z1 and Z2 are independently selected from CH and C (wherein one substituent is attached), X is C, ring B is saturated heterocyclyl shown in the structure below and R1, R2, R3, and R4 are as defined in the Summary, can be prepared by the following procedure described in Scheme 3.

Reaction of a compound of formula 1 in which -alk-R1, R2 and R3 are as defined in the Summary or a parent group thereof, with an unsubstituted or substituted 5-, 6- or 7-membered heterocycloalkyl compound of formula 9 with Rj, Rk, Rl and/or Rm as defined in the Summary, for example, pyrrolidine-3-carboxylic acid, 2-oxopiperidine-3-carboxylic acid, or 2-oxoazepan-3-carboxylic acid where PG is a suitable nitrogen protecting group (such as benzyl, p-methoxybenzyl or Boc) in the presence of an amide coupling agent (such as 1-[bis(dimethylamino)-methylene]-1H-1,2 3-oxide hexafluorophosphate, 3-triazolo[4,5-b]pyridinium (HATU) and hydroxybenzotriazole (HOBt), 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide (EDCI) and HOBt, or benzotriazol-1-yloxytripyrrolidin phosphonium hexafluorophosphate (PyBOP)) in an appropriate solvent (such as dimethylformamide (DMF) or 1,4-dioxane) at room temperature yields compound 10.

Compounds of formula 9 can be prepared as shown below:

Compounds of formula 9 can be prepared from a 5-, 6-, or 7-membered heterocyclyl compound of formula 13 by deprotonation of compound 13 with a suitable base such as tBuLi or lithium diisopropylamide (LDA) followed by treatment with CO2 gas ( see Zhang et al., Organic Letters, 2016, 18(3):348-351 for a representative method). Compounds of formula 13 such as 1-benzyl-2-pyrrolidinone and 1-benzylpiperidin-2-one are commercially available. Compounds of formula 13 can also be prepared by capping the nitrogen atom of a commercially available lactam of formula 12 (such as azepan-2-one, 2-piperidinone, 6-methyl-2-piperidinone, 6,6-dimethylpiperidin-2- one and 5,5-dimethylpyrrolidin-2-one), for example, by reacting 12 under alkylation reaction conditions (such as with benzyl chloride (BnCl) or p-methoxybenzyl chloride (PMBCl) under a hydride-mediated condition sodium (NaH) or potassium carbonate (K2CO3) in appropriate solvents such as tetrahydrofuran (THF) or dimethylformamide (DMF) Compounds of formula 13 in which Pg is Boc can be obtained by treatment of a lactam of formula 12 (such as azepan-2-one, 2-pyrrolidinone, 2-piperidinone, 6-methyl-2-piperidinone, 6,6-dimethylpiperidin-2-one, 5,5-dimethylpyrrolidin-2-one, etc.) with dicarbonate of ditert-butyl in the presence of 4-dimethylaminopyridine in a solvent suitable solvents, such as acetonitrile or dimethylpho rmamide (DMF).

Alternatively, the compounds of formula 9 can be prepared by hydrolysis of the ester group in the compounds of formula 14 with a base, such as sodium hydroxide (NaOH) or lithium hydroxide (LiOH). Compounds of formula 14 can be prepared by deprotonation of compound 12 with bases, such as tBuLi or lithium diisopropylamide (LDA), followed by treatment with dimethyl carbonate.

Treatment of compound 10 with POCl3 at 90 °C at reflux for up to 16 h provides a compound of formula 11a where R4 is chlorine (when PG is Boc or methoxybenzyl) or formula 11b (when PG is benzyl) . Removal of the amino protecting group in 11b provides a compound of formula 11a. Compounds of formula 11a can be converted to compounds of formula (I) as described herein.

Compounds of Formula (I) in which Z1 is N, Z2 is CH or C (wherein a substituent is attached), X is C and ring B, R1, R2, R3 and R4 are as defined in Summary, they can be prepared by the following procedure described in Scheme 4 below.

Scheme 4

Reaction of a compound of formula 15 in which -alk-R1, R2 and R3 are as defined in the Summary or a parent group thereof, with a compound of formula 4 under the reaction conditions described in Scheme 2 provides a compound of formula 16. Compounds of formula 15 can be prepared by methods well known in the art. For example, 2-bromo-6-methoxy-3-nitro-5-[3-(pyrrolidin-1-yl)propoxy]pyridine and 6-bromo-2-methoxy-5-nitro-N-[3 -(pyrrolidin-1-yl)propyl]pyridin-3-amine from commercially available 3-hydroxy-pyridine and 3-aminopyridine by methods known to those skilled in the art (see literature procedures such as Australian Journal of Chemistry, 1981, 34(4):927-932; Bioorganic and Medicinal Chemistry Letters, 2014, 24(24):5630-5634; WO 2008/101682 A2, and Journal of Heterocyclic Chemistry, 1972, 9:1039-1043) . Compound 16 can be converted to the compound of formula (I) where R4 is hydroxy as described in Scheme 2 herein and another compound of formula (I) as described in Scheme 1 herein.

Alternatively, compound 15 can be converted to a compound of Formula (I) following the method illustrated in Methods (i) and (ii) herein.

In Method (i), Compound 15 is first converted to a compound of formula 17 where Y is 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl-, -B(OH)2, -tributylstannyl, or other appropriate functional groups. Compound 17 is then reacted with a compound of formula 7 as described in Scheme 2 herein to provide a compound of formula 16, which after reduction of the nitro group, ester hydrolysis, and coupling reaction of intramolecular amide provides the compound of formula (I) (wherein R4 is hydroxy) which can be converted to another compound of Formula (I) as described above in Scheme 1.

In Method (ii), compound 15 is converted to a compound of formula 18 (wherein P1 and P2 are independently selected from H and Boc) by reduction of the nitro group with a suitable reducing agent, such as tin chloride (II), followed by reaction of the resulting amino compound 18 (where P1 and P2 are each hydrogen) with di-tert-butyl dicarbonate in the presence of 4-dimethylaminopyridine to provide the corresponding compound 18 (where P1 and /or P2 is Boc). Compound 18 is reacted with compound 4 under conditions similar to those described above in Scheme 2 to provide a compound of formula 19 which is then converted to a compound of formula (I) where R4 is hydroxy after elimination of the amino protecting group(s) and/or intramolecular amide coupling, if necessary, as described above. The compound of formula (I) in which R4 is hydroxy is further transformed into the compound of formula (I) in which R4 is another appropriate group following a procedure similar to that described above.

Compounds of Formula (I) in which Z1 is N, CH or C, Z2 is N, X is C and ring B, R1, R2, R3 and R4 are as defined in the Summary, can be prepared by the following procedure described in Scheme 5.

The reaction of a compound of formula 20 (wherein -alk-R1, R2 and R3 are as defined in the Summary or a parent group thereof, and Z1 is N, C or CH), with a compound of formula NHPG1PG2 (wherein PG1 and PG2 are H or a suitable nitrogen protecting group such as benzyl, p-methoxybenzyl, or Boc), followed by coupling reaction of the resulting amino compound 21 with compound 4 under the reaction conditions described in herein, provide a compound of formula 22. Removal of the amino protecting groups (for example, with an acid such as TFA or HCl when PG1 and/or PG2 is -p-methoxybenzyl) provides a compound of formula 23, which is can be converted to a compound of formula (I) subsequently by hydrolysis of the ester (for example, with a base such as NaOH or LiOH, when R' is alkyl) and intramolecular amide coupling reaction under the conditions described herein if it is necessary. In some cases, intermediate compound 23 (wherein R' is not H) may cyclize directly to the compound of formula (I). Compounds of formula 20 (such as 2,3-dichloro-5-methoxy-6-[3-(pyrrolidin-1-yl)propoxy]pyridine and 2,3-dichloro-5-methoxy-6-[3-( pyrrolidin-1-yl)propoxy]pyrazine) can be prepared from commercially available material, such as perchloropyrazine and 2,3,5,6-tetrachloropyridine, by methods known to those skilled in the art. Other compounds of formula 20 can also be prepared from the starting material, such as 5,6-dimethoxypyridin-2-amine, 6-amino-5-chloro-3-(trifluoromethoxy)pyridin-2-ol, 6-amino -5-chloro-2-(trifluoromethoxy)pyridin-3-ol, 2,5-dichloro-6-methyl-nicotinonitrile, and 5,6-dichloronicotinonitrile through procedures known to those skilled in the art.

Tests

The G9a inhibitory activity of the compounds of the present disclosure can be tested using the in vitro assay described in Biological Example 1 below. The ability of the compounds of the disclosure to stimulate fetal hemoglobin can be tested using the in vitro assay described in Biological Example 2 below.

Administration and Pharmaceutical Composition

In general, the compounds of this disclosure will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents having similar utilities. Therapeutically effective amounts of the compounds of this disclosure may range from about 0.01 to about 500 mg per kg of subject body weight per day, which may be administered in single or multiple doses. A suitable dosage level may be from about 0.1 to about 250 mg/kg per day or from about 0.5 to about 100 mg/kg per day. A suitable dosage level may be from about 0.01 to about 250 mg/kg per day, from about 0.05 to about 100 mg/kg per day, or from about 0.1 to about 50 mg/kg per day. Within this range, the dosage may be from about 0.05 to about 0.5, from about 0.5 to about 5, or from about 5 to about 50 mg/kg per day. For oral administration, the compositions may be provided in the form of tablets containing from about 1.0 to about 1000 milligrams of the active ingredient, in particular about 1, 5, 10, 15, 20, 25, 50.

75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, or 1,000 milligrams of the active ingredient. The actual amount of the compound of this disclosure, that is, the active ingredient, will depend on numerous factors such as the severity of the disease being treated, the age and relative health of the subject, the potency of the compound being used, the route and form of administration, and other factors.

In general, the compounds of this disclosure will be administered as pharmaceutical compositions by any of the following routes: oral, systemic (eg, transdermal, intranasal, or by suppository), or parenteral (eg, intramuscular, intravenous, or subcutaneous) administration. ). The preferred form of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. The Compositions may take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable composition.

The choice of formulation depends on several factors such as the mode of administration of the drug (eg, for oral administration, formulations in the form of tablets, pills, or capsules are preferred, including coated tablets, pills, or capsules). enteral or delayed release) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs showing poor bioavailability based on the principle that bioavailability can be increased by increasing the surface area, ie, by decreasing the particle size. For example, US Patent No. 4,107,288 describes a pharmaceutical formulation having particles in the size range of 10 to 1,000 nm in which the active material is supported on a cross-linked matrix of macromolecules. US Patent No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size 400nm) in the presence of a surface modifier and then dispersed in a medium. liquid to provide a pharmaceutical formulation that exhibits remarkably high bioavailability.

Compositions generally comprise a compound of this disclosure in combination with at least one pharmaceutically acceptable carrier. Acceptable excipients are non-toxic, aid in administration, and do not adversely affect the therapeutic benefit of the compound of this disclosure. Such excipient may be any solid, liquid, semi-solid, or, in the case of an aerosol composition, gaseous excipient that is generally available to one skilled in the art.

Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, nonfat milk, powder and the like. Liquid and semi-solid excipients can be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil , etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

Compressed gases can be used to disperse a compound of this disclosure in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.

Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th edition, 2000).

The level of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt%) basis, from about 0.01-99.99% by weight of a compound of this disclosure based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. For example, the compound is present at a level of about 1-80% by weight.

The compounds of this disclosure may be used in combination with one or more drugs in the treatment of diseases or conditions for which the compounds of this disclosure or the other drugs may have utility. Said other drug(s) may be administered, by a route and in an amount commonly used therefor, at the same time or sequentially with a compound of the present disclosure. When a compound of this disclosure is used concurrently with one or more other drugs, a pharmaceutical composition in unit dosage form containing said other drugs and the compound of this disclosure is preferred. However, combination therapy can also include therapies in which the compound of this disclosure and one or more drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more active ingredients, the compounds of the present disclosure and the other active ingredients may be used at lower doses than when each is used individually.

Accordingly, the pharmaceutical compositions of the present disclosure also include those that contain one or more drugs, in addition to a compound of the present disclosure.

The above combinations include combinations of a compound of this disclosure with not only another drug, but also two or more active drugs. Likewise, a compound of this disclosure may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of the risk of diseases or conditions for which a compound of this disclosure is useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, at the same time or sequentially with a compound of the present disclosure. When a compound of this disclosure is used concurrently with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of this disclosure may be used. Accordingly, the pharmaceutical compositions of the present disclosure also include those that also contain one or more active ingredients, in addition to a compound of this disclosure. The weight ratio of the compound of this disclosure to the second active ingredient may vary and will depend on the effective dose of each ingredient. Generally, an effective dose of each will be used.

When the subject in need thereof has or is at risk of cancer, the subject may be treated with a compound of this disclosure in any combination with one or more anti-cancer agents and/or anti-cancer therapies. In some embodiments, the anticancer therapies may be surgery and/or radiation therapy. In some embodiments, one or more of the anticancer agents are proapoptotic agents. Examples of anticancer agents include, but are not limited to, any of the following: gossypol, genasense, polyphenol E, chlorofusin, all-trans retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5- aza-2'-deoxycytidine, all-trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (GleevecMC), geldanamycin, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412 or PD184352, Taxol™, also known as "paclitaxel", which is a well-known anticancer drug that acts by enhancing and stabilizing microtubule formation, and Taxol™ analogs, such as docetaxel (Taxotere™). Compounds having the basic taxane backbone as a common structural feature have also been shown to have the ability to arrest cells in G2-M phases due to stabilized microtubules and may be useful in treating cancer in combination with the described compounds. in the present document.

Other examples of anticancer agents for use in combination with a compound of this disclosure include inhibitors of mitogen-activated protein kinase signaling, eg, U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006 , wortmannin or LY294002; Syk inhibitors; antibodies (eg, rituxan); MET inhibitor such as foretinib, carbozantinib, or crizotinib; VEGFR inhibitor such as sunitinib, sorafenib, regorafinib, lenvatinib, vandetanib, carbozantinib, or axitinib; EGFR inhibitor such as afatinib, brivanib, carbozatinib, erlotinib, gefitinib, neratinib, or lapatinib; PI3K inhibitor such as XL147, XL765, BKM120 (buparlisib), GDC-0941, BYL719, IPI145, BAY80-6946, BEX235 (dactolisib), CAL101 (idelalisib), GSK2636771, or TG100-115; MTOR inhibitor such as rapamycin (sirolimus), temsirolimus, everolimus, XL388, XL765, AZD2013, PF04691502, PKI-587, BEZ235, or GDC0349; MEK inhibitor such as AZD6244, trametinib, PD184352, pimasertinib, GDC-0973, or AZD8330; and proteasome inhibitor such as carfilzomib, MLN9708, delanzomib, or bortezomib.

Other anticancer agents that can be used in combination with a compound of this disclosure include adriamycin; dactinomycin; bleomycin; vinblastine; cisplatin; acivicin; aclarubicin; Acodazole Hydrochloride; acronin; adozelesin; aldesleukin; altretamine; ambomycin; Amethantrone Acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlina; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; sodium brequinar; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; chrysnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; Daunorubicin Hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; Doxorubicin Hydrochloride; droloxifen; Droloxifene Citrate; Dromostanolone Propionate; duazomycin; edatrexate; Eflornithine Hydrochloride; elsamitrucin; enloplatin; promote; epipropidine; Epirubicin Hydrochloride; erbulozole; Esorubicin Hydrochloride; estramustine; Estramustine Sodium Phosphate; ethanidazole; etoposide; etoposide phosphate; etoprine; Fadrozole Hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; phosphidone; sodium fostriecin; gemcitabine; Gemcitabine Hydrochloride; hydroxyurea; Idarubicin Hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II or Ri12), interferon alfa-2a; interferon alfa-2b; interferon alfa-nl; interferon alpha-n3; interferon beta-1a; interferon gamma-1b; iproplatin; Irinotecan Hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; Liarozole Hydrochloride; lometexole sodium; lomustine; Losoxantrone Hydrochloride; masoprocol; maytansine; Mechlorethamine Hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; sodium methotrexate; methoprine; meturedepa; mitindomide; mitocarcin; mitochromin; mitogyline; mitomalcin; mitomycin; mitosper; mitotane; Mitoxantrone Hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxysuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perphosphamide; pipobroman; piposulfan; Pyroxantrone Hydrochloride; plicamycin; plumbote; sodium porfimer; porphyromycin; prednimustine; Procarbazine Hydrochloride; puromycin; Puromycin Hydrochloride; Pyrazofurin; riborrhine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sodium sparphosate; sparsemycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; sodium tecogalan; tegafur; Teloxantrone Hydrochloride; thermoporfin; teniposide; Teroxirone; testolactone; Thiamiprine; thioguanine; thiotepa; Thiazofurin; tirapazamine; Toremifene Citrate; Trestolone Acetate; Tricyribine Phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; Tubulozole Hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinylurosine sulfate; Vinorelbine Tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicin hydrochloride.

Other anticancer agents that can be used in combination with a compound of the disclosure such as 20-epi- analogs of 1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecipenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; antidorsalizing morphogenetic protein 1; antiandrogen, prosthetic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; Axinastatin 2; axinastatin 3; azasetrone; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorines; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; Bfgf inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breaplate; bropirimine; budotitan; butionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; IL-2 canarypox; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; MEAT 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; Chloroquinoxaline Sulfonamide; cicaprost; cis-porphyrin; cladribine; clomiphene analogs; clotrimazole; colimycin A; colimycin B; Combretastatin A4; combretastatin analog; congenin; crambescidin 816; chrysnatol; cryptooffice 8; cryptophycin A derivatives; curacin A; cyclopentantraquinones; cycloplatam; cipemicin; cytarabine ocphosphate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; Deslorelin; dexamethasone; dexyphosphamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnospermine; dihydro-5-azacytidine; 9-dioxamycin; spiromustine diphenyl; docosanol; dolasetrone; doxifluridine; droloxifen; dronabinol; duocarmycin SA; ebselene; ecomustine; edelfosine; edrecolomab; Eflomitin; element; emitfur; epirubicin; episteride; estramustine analog; estrogen agonists; estrogen antagonists; ethanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; Fluorodaunorubicin Hydrochloride; forphenimex; formestane; fostriecin; fotemustine; Gadolinium Texaphyrin; gallium nitrate; gallocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfame; heregulin; hexamethylenebisacetamide; hypericin; Ibandronic Acid; idarubicin; idoxifen; Idramantone; ilmofosine; ylomastat; imidazoacridones; imiquimod; immunostimulatory peptides; insulin-like growth factor 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iodoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibitory factor; leukocyte interferon alpha; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analog; lipophilic disaccharide peptide; lipophilic platinum compounds; lysoclinamide 7; lobaplatinum; vermicine; lometrexol; lonidamine; losoxantrone; lovastatin; loxorribine; lurtotecan; lutetium texaphyrin; lysophylline; lytic peptides; maytansine; mannostatin A; marimastat; masoprocol; maspine; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirímostim; unpaired double-stranded RNA; mitoguazone; mitolactol; mitomycin analogs; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotropin; monophosphoryl lipid A+ diethylstilbene cell wall sk; mopidamol; multidrug resistance gene inhibitor; multiple tumor suppressor 1-based therapy; mustard anticancer agent; miperoxide B; mycobacteria cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavine; naafterpine; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitruline; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetrone; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrizoxine; pamidronic acid; panoxytriol; panomiphene; parabactin; pazeliptin; pegaspargase; peldesina; sodium pentosan polysulfate; pentostatin; pentrozole; perflubrone; perphosphamide; peryl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; Pilocarpine Hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; sodium porfimer; porphyromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immunomodulator; protein kinase C inhibitors, microalgae; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; glitters; pyrazoloacridine; pyridoxylated polyoxyethylene hemoglobin conjugate; raf antagonists; raltitrexed; ramosetrone; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; demethylated reteliptin; rhenium etidronate Re 186; rhizoxin; ribozymes; retinamide R11; rogletimide; rohitukine; broken; roquinimex; Rubiginone B1; ruboxyl; safingol; santopine; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derivative 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin-binding protein; sonermine; sparphosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; Suradist; suramin; Swainsonine; synthetic glycosaminoglycans; talimustine; Tamoxifen Methiodide; tauromustine; Tazarotene; sodium tecogalan; tegafur; tellurapyrylium; telomerase inhibitors; thermoporfin; temozolomide; teniposide; tetrachlorodecoxide; tetrazomine; taliblastin; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymothrin; thyroid stimulating hormone; tin ethyl ethiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; candlesol; veramine; verdigris; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin estimalamer.

Still other anticancer agents that may be employed in combination with a compound of this disclosure include alkylating agents, antimetabolites, natural products, or hormones, for example, nitrogen mustards (eg, mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (eg, busulfan, etc.), nitrosoureas (eg, carmustine, lomustine, etc.), or triazenes (decarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (eg, methotrexate), pyrimidine analogs (eg, cytarabine, etc.), or purine analogs (eg, mercaptopurine, thioguanine, pentostatin, etc).

Examples of natural products useful in combination with a compound of this disclosure include, but are not limited to, vinca alkaloids (eg, vincristine, etc.), epipodophyllotoxins (eg, etoposide, etc.), antibiotics ( daunorubicin, doxorubicin, bleomycin, etc.), enzymes (eg, L-asparaginase, etc.), or biological response modifiers (eg, interferon alpha, etc.).

Examples of alkylating agents that may be employed in combination with a compound of this disclosure include, but are not limited to, nitrogen mustards (eg, mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethyleneimine, and methylmelamines (eg, eg, hexamethylmelamine, thiotepa, etc.), alkyl sulfonates (eg, busulfan, etc.), nitrosoureas (eg, carmustine, lomusitne, semustine, streptozocin, etc.), or triazenes (decarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (eg, methotrexate, etc.), pyrimidine analogs (eg, fluorouracil, floxuridine, cytarabine, etc.), or purine analogs (eg. g., mercaptopurine, thioguanine, pentostatin, etc.)

Examples of hormones and antagonists useful in combination with a compound of this disclosure include, but are not limited to, adrenocorticosteroids (eg, prednisone, etc.), progestins (eg, hydroxyprogesterone caproate, megestrol acetate, and medroxyprogesterone, etc.), estrogens (eg, diethylstilbestrol and ethinylestradiol, etc.), antiestrogens (eg, tamoxifen, etc.), androgens (eg, testosterone propionate, fluoxymesterone, etc.) , antiandrogens (eg, flutamide, etc.) and gonadotropin-releasing hormone analog (eg, leuprolide, etc.). Other agents that can be used in the methods and compositions described herein for the treatment or prevention of cancer include platinum coordination complexes (eg, cisplatin, carboplatin, etc.), anthracenedione (eg, mitoxantrone, etc.), substituted urea (eg, hydroxyurea, etc.), methylhydrazine derivatives (eg, procarbazine, etc.), and adrenocortical suppressant (eg, mitotane, aminoglutethimide, etc.) .

Examples of anticancer agents that act by arresting cells in G2-M phases due to stabilized microtubules and that can be used in combination with an irreversible Btk inhibitor compound include, without limitation, the following drugs on the market and drugs in development: Erbulozol (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128), Mivobulin Isethionate (also known as CI-980), Vincristine, NSC-639829, Discodermolide (also known as NVP-XX -A-296), AbT-751 (Abbott, also known as E-7010), Altorirtins (such as Altorirtin A and Altorirtin C), Spongistatins (such as Spongistatin1, Spongistatin2, Spongistatin3, Spongistatin4, Spongistatin 5, Spongistatin 6, Spongistatin 7 , spongistatin 8 and spongistatin 9), cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356), epothilones (such as epothilone A, epothilone B, epothilone C (also known as deoxypothilone a A or dEpoA) ), epothilone D (also known as KOS-862, dEpoB and deoxypothilone B), Epothilone E, Epothilone F, epothilone B N-oxide, epothilone A N-oxide, 16-aza-epothilone B, 21-Aminoepothilone B (also known as BMS-310705), 21-Hydroxyepothilone D (also known as deoxyepothilone F and dEpoF), 26-Fluoroepothilone, Auristatin PE (also known as NSC-654663), Soblidotin (also known as TZT-1027 ), lS-4559-P (Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR- 112378 (Aventis), Vincristine Sulfate, DZ-3358 (Daiichi), Fr -182877 (Fujisawa, aka WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy Science), BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (also (known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39 -L -Be. HCl and RPR-258062A), Vitilevuamide, Tubulisin A, Canadensol, Centaureidine (also known as NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067), Co BrA-1 (Parker Hughes Institute, also known as DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A1 (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B. Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, aka SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai School of Medicine, aka MF -569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlina, 3-BAa Bu (Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-191), TMPN (Arizona State University), Vanadocene Acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocin (also known as NSC-698666), 3-1AABE (Cytoskeleton/Mt. Sinai Scho ol of Medicine), A-204197 (Abbott), T-607 (Tuiarik, aka T-900607), r Pr-115781 (Aventis), Eleutherobins (as Desmethyleleutherobin, Desaethyleleuterobin, Isoeleutherobin A, and Z-Eleutherobin), Caribaeoside , Caribaeolin, Halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Tacalonolide A, Tu B-245 (Aventis), A-259754 (Abbott), Diozostatin, (-)-Phenylahistin (also known as NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Mioseverin B, D-43411 (Zentaris, also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI -286 (also known as SPA 110. trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), resverastatin sodium phosphate, BPR-OY-007 (National Health Research Institutes), and s Sr -250411 (Sanofi).

examples

The following preparations of compounds of Formula (I) (Examples) and intermediate compounds (References) are provided to enable those skilled in the art to more clearly understand and practice the present disclosure. They should not be considered as limiting the scope of the disclosure, but simply as illustrative and representative thereof.

Intermediate Compound I-1 Intermediate Compound I-2 Intermediate Compound I-3

Intermediate Compound I-4 Intermediate Compound I-5 Intermediate Compound I-6

Intermediate II-1 Intermediate II-2 Intermediate II-3

Intermediate II-4 Intermediate II-5 Intermediate II-6

Intermediate III-1 Intermediate III-2 Intermediate III-3

Intermediate III-4 Intermediate III-5 Intermediate III-6

Intermediate Compound 111-13 Intermediate Compound 111-14 Intermediate Compound III-15

Reference 1

Synthesis of 1-[3-(2-methoxy-5-nitrophenoxy)propyl]pyrrolidine (Intermediate Compound I-1)

In a 250 mL round bottom flask was placed a mixture of 2-methoxy-5-nitrophenol (5.00 g, 29.56 mmol, 1.00 eq.), N,N-dimethylformamide (60 mL), potassium carbonate (8.10 g, 58.61 mmol, 2.00 eq.) and 1-(3-chloropropyl)pyrrolidine (5.99 g, 40.57 mmol, 1.10 eq.). The resulting mixture was allowed to stir at 80 °C for 12 h. The reaction mixture was cooled to rt, diluted with H2O and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel with 10% MeOFUCH2Cl2 as eluent to give 1-[3-(2-methoxy-5-nitrophenoxy)propyl]pyrrolidine as a yellow oil (4.80 g, 58%) . LCMS (ES) [M+1]+m/z 281. Reference 2

Synthesis of 4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline (Intermediate Compound I-2)

In a 250 mL round bottom flask, a mixture of 1-[3-(2-methoxy-5-nitrophenoxy)-propyl]pyrrolidine (Intermediate I-1) (4.80 g, 17.12 mmol, 1.00 eq. ), methanol (100 mL), and 10% Pd/C (500 mg). The flask is degassed and purged with H25 times. The mixture was left under stirring under H2 atmosphere at room temperature for 4 h and the solid was filtered off. Removal of organic solvents under reduced pressure gave 4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline as a tan oil (4.10 g, 96%). LCMS (ES) [M+1]+ m/z 251.2.

Reference 3

Synthesis of 1-[3-(4-bromo-2-methoxyphenoxy)propyl]pyrrolidine (Intermediate Compound I-3)

In a 1 L round bottom flask, a mixture of 4-bromo-2-methoxyphenol (15.0 g, 73.88 mmol, 1.00 eq.), N,N-dimethylformamide (300 mL), 1-(Hydrochloride of 3-chloropropyl)pyrrolidine (13.60 g, 73.88 mmol, 1.00 eq.), potassium iodide (12.26 g, 73.88 mmol, 1.00 eq.), and potassium carbonate (20.4 g, 147, 76 mmol, 2.00 eq.). The resulting mixture was allowed to stir for 5 hours at 70°C. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with dichloromethane/methanol (6/1) to give 1-[3-(4-bromo-2-methoxyphenoxy)propyl]pyrrolidine (Intermediate I-3) as a brown oil. (18.5g, 80%). LCMS (ES) [M+1]+m/z 314.0.

Reference 4

Synthesis of 1-[3-(4-bromo-2-methoxy-5-nitrophenoxy)propyl]pyrrolidine (Intermediate Compound I-4)

Into a 500 mL 3-necked round-bottomed flask was placed a solution of 1-[3-(4-bromo-2-methoxyphenoxy)propyl]pyrrolidine (Intermediate I-3) (18.0 g, 57.29 mmol, 1.00 eq.) in acetic acid (100 mL). HNO3 (50 mL) was added dropwise to the stirring solution at 15 °C. The resulting solution was allowed to stir for 3 hours at 25°C. The reaction was then quenched by the addition of ice water. The precipitate was collected by filtration to give 1-[3-(4-bromo-2-methoxy-5-nitrophenoxy)propyl]pyrrolidine as a yellow solid (18.1 g, 88%). LCMS (ES) [M+1]+ m/z 359.0.

Reference 5

Synthesis of 1-{3-[4-(4,4-dimethyl-1,3,2-dioxaborolan-2-yl)-2-methoxy-5-nitrophenoxy]-propyl}pyrrolidine (Intermediate I-5)

Into a 500 mL 3-necked round bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a mixture of 1-[3-(4-bromo-2-methoxy-5-nitrophenoxy)propyl]pyrrolidine ( Intermediate 1-4) (8.0 g, 22.27 mmol, 1.00 eq.), 1,4-dioxane (200 mL), BPD (8.51 g, 33.51 mmol, 1.50 eq.), KOAc (4.38 g, 44.63 mmol, 2.00 eq.) and Pd(dppf)Cl2 (1.63 g, 2.23 mmol, 0.10 eq.). The resulting mixture was allowed to stir under N2 atmosphere at 110 °C for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with dichloromethane/methanol (10/1) to give 1-{3-[4-(4,4-dimethyl-1,3,2-dioxaborolan-2- yl)-2-methoxy-5-nitrophenoxy]propyl}pyrrolidine (Intermediate I-5) as a gray solid (6.1 g, 67%). LCMS (ES) [M+1]+ m/z 407.2.

Reference 6

Synthesis of 2-fluoro-4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline (Intermediate I-6)

Stage 1

In a 250 mL round bottom flask, a mixture of 2-fluoro-6-methoxyphenol (4.6 g, 32.36 mmol, 1.00 eq.), acetonitrile (150 mL), 3-(pyrrolidin-1-yl )propan-1-ol (10.73 g, 58.26 mmol, 1.80 eq.), potassium carbonate (12.3 g, 89.00 mmol, 2.75 eq.), and potassium iodide (9.67 g, 58.26 mmol, 1.80 eq.). The resulting mixture was allowed to stir at 80 °C for 3 h. The solids were filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with ethyl acetate/petroleum ether (1/3) to give 1-[3-(2-fluoro-6-methoxyphenoxy)propyl]pyrrolidine as a yellow solid. (4.35g, 53%). LCMS (ES) [M+1]+ m/z 254.1.

Stage 2

To a 50 mL round bottom flask placed in an ice bath at 0 °C was added 1-[3-(2-fluoro-6-methoxyphenoxy)propyl]pyrrolidine (4.35 g, 17.17 mmol, 1.00 eq.). To the resulting mixture, nitric acid (10 mL) was slowly added. The resulting solution was allowed to stir at room temperature for 1 hour. The reaction mixture was poured into ice water (50 mL). The pH value of the solution was adjusted to 8 with sodium bicarbonate aqueous solution (1.0 M). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with ethyl acetate/petroleum ether (1/5) to give 1-[3-(2-fluoro-6-methoxy-3-nitrophenoxy)propyl]pyrrolidine as a yellow oil (1.52 g, 30%). LCMS (ES) [M+1]+ m/z 299.2.

Stage 3

In a 100 mL round bottom flask, a mixture of 1-[3-(2-fluoro-6-methoxy-3-nitrophenoxy)propyl]pyrrolidine (1.52 g, 5.10 mmol, 1.00 eq. ), methanol (30 mL), and 10% Pd/C (500 mg). The mixture was degassed and purged three times with hydrogen. The resulting mixture was allowed to stir under an atmosphere of H2 at room temperature for 2 h. The reaction mixture was diluted with MeOH (50 mL) and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give 2-fluoro-4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline Intermediate-6) as a yellow oil (1.27 g, 93%) . LCMS (ES) [M+1]+ m/z 269.2.

Reference 7

Synthesis of 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine (Intermediate II-1)

In a 50 ml round bottom flask was placed a mixture of 8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-ol (Example 37 below) (346 mg, 1.01 mmol, 1.00 eq.) and POCl3 (4.5 mL). The resulting solution was allowed to stir at 100 °C for 2 h. After removing volatiles under reduced pressure, the residue was poured into water. The mixture was adjusted with aqueous sodium bicarbonate solution (2N) to pH=8 and extracted three times with CH2Cl2. The combined organic layers were dried over anhydrous sodium sulfate. The solid was filtered off and the solution was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel with 25% MeOFUCH2Cl2 (0.1% NH4OH) as eluant to give the desired product (Intermediate II-1) as a yellow solid (214 mg, 59%). LCMS (ES) [M+1]+ m/z 361.2.

Reference 8

Synthesis of 6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine

(Intermediate compound II-2)

The title compound was prepared from 2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-6-ol (Example 38 below) following a procedure similar as described for the synthesis of Intermediate II-1 above. The crude product was purified by flash column chromatography on silica gel with 25% MeOFUCH2Cl2 (0.1% NH4OH) as eluent to provide the desired product as a brown solid. LCMS (ES) [M+1]+ m/z 375.2.

Reference 9

Synthesis of 1-[3-({4-chloro-8-methoxy-2-methyl-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate II-3)

Stage 1

In a -78 °C solution of 3-methylcyclopent-2-en-1-one (14.40 g, 150.0 mmol, 1.0 eq.) in tetrahydrofuran (200 mL) under N2 atmosphere, lithium diisopropylamide (LDA) was added ( 150 mL, 2.0 M in THF, 300.0 mmol, 2.00 eq.) for 20 min. The resulting solution was allowed to stir at -78 °C for 1 h. A solution of dimethyl carbonate (14.85 g, 165.0 mmol, 1.10 eq.) in THF (150 mL) was added dropwise over 20 min. The resulting solution was allowed to warm from -78 °C to rt and allowed to stir for an additional 3 h. The reaction mixture was poured into aqueous HCl solution (1.0 N) at 0 °C. The organic layer was separated. The water layer was re-extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with ethyl acetate/petroleum ether (1/1) to give methyl 4-methyl-2-oxocyclopent-3-ene-1-carboxylate as an oil of light brown color (6.13 g, 27%). LCMS (ES) [M+1]+ m/z 155.1.

Stage 2

In a 250 mL round bottom flask was placed a mixture of methyl 4-methyl-2-oxocyclopent-3-ene-1-carboxylate (6.13 g, 39.81 mmol, 1.00 eq.), methanol (100 mL), and Pd /C 10% (400 mg). The flask was flushed with nitrogen three times, followed by hydrogen twice. The mixture was left under stirring under hydrogen atmosphere at room temperature for 1 hour. The solids were filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with ethyl acetate/petroleum ether (1/2) to give methyl 4-methyl-2-oxocyclopentane-1-carboxylate as a colorless oil (3.87 g, 62%). LCMS (ES) [M+1]+ m/z 157.2.

Stage 3

The title compound was prepared from methyl 4-methyl-2-oxocyclopentane-1-carboxylate and 4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline (Intermediate I-2) by following Similar conditions as described in Example 37 below and Reference 7 above, except that the final crude product was purified by flash column chromatography on silica gel eluted with dichloromethane/methanol (8/1) to give the desired product as a light brown solid. LCMS (ES) [M+1]+ m/z 375.2.

Reference 10

Synthesis of 1-[3-({4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate II-4 )

The title compound was prepared from methyl 4,4-dimethyl-2-oxocidopentane-1-carboxylate (prepared according to the literature procedure reported in Organic Letters, 2004, Vol 6, No. 24, pages 44 l l -4414) and 4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline (Intermediate Compound I-2) following a procedure similar to that described in Reference 9 above, except that the final crude product is purified by flash column chromatography on silica gel eluted with 10-20% MeOH/dichloromethane (0.1% NH4OH) to give the title product as a light brown solid. LCMS (ES) [M+1]+ m/z 389.2.

Reference 11

Synthesis of 3-[({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)methyl]-1-methylpyrrolidine (Intermediate II-5)

Stage 1

In a 500 mL round bottom flask was placed a solution of methyl 2-oxocyclopentane-1-carboxylate (14.2 g, 99.89 mmol, 1.00 eq.), toluene (150 mL), ethane-1,2-diol ( 12.4 g, 199.78 mmol, 2.00 eq.) and TsOH (860 mg, 4.99 mmol, 0.05 eq.). The solution was refluxed overnight. The reaction mixture was cooled to room temperature, diluted with water (100 ml) and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with 25% ethyl acetate/petroleum ether (1/3) to give methyl 1,4-dioxaspiro[4.4]nonane-6-carboxylate as a colorless oil (6.5 g. 35%).

Stage 2

In a 100 mL round bottom flask was placed a solution of methyl 1,4-dioxaspiro[4.4]-nonane-6-carboxylate (6.5 g, 34.9 mmol, 1.00 eq.), methanol (60 mL), water (30 mL) and sodium hydroxide (2.78 g, 69.7.00 mmol, 2.00 eq.). The resulting solution was allowed to stir at 80 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was diluted with water and treated with saturated aqueous NaH2PO4 solution at pH=5~6). The mixture was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1,4-dioxaspiro[4.4]nonane-6-carboxylic acid as a white solid (3.94 g, 66%).

Stage 3

In a 250 mL round bottom flask, purged and kept under a nitrogen atmosphere, was placed a solution of 2-methoxy-5-nitrophenol (5.0 g, 29.56 mmol, 1.00 eq.), dichloromethane (70 mL), (1 -methylpyrrolidin-3-yl)methanol (6.8 g, 59.09 mmol, 2.00 eq.) and PPh3 (15.5 g, 59.09 mmol, 2.00 eq.). To this stirring solution a solution of di-t-butyl azodicarboxylate (13.6 g, 59.09 mmol, 2.00 eq.) in dichloromethane (30 mL) was added dropwise at 0 °C under N2. The resulting solution was allowed to stir for 4 hours at room temperature and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with MeOH/CH2Cl2 (1/8) to give 3-(2-methoxy-5-nitrophenoxymethyl)-1-methylpyrrolidine as a pale yellow solid (5.5 g, 70 %). LCMS (ES) [M+1]+ m/z 267.1.

Stage 4

[0097] In a 250 mL round bottom flask, a mixture of 3-(2-methoxy-5-nitrophenoxy-methyl)-1-methylpyrrolidine (5.5 g, 20.65 mmol, 1.00 eq.), methanol (100 ml) and 10% Pd/C (500 mg). The flask was flushed with nitrogen three times followed by hydrogen twice. The mixture was left under stirring under H2 atmosphere at room temperature overnight. The solids were filtered off. The filtrate was concentrated under reduced pressure to give 4-methoxy-3-[(1-methylpyrrolidin-3-yl)methoxy]aniline as light brown oil (4.8 g, 98%). LCMS (ES) [M+1]+ m/z 237.2.

Stage 5

In a 250 mL round-bottom flask, a solution of 1,4-dioxaspiro[4.4]nonane-6-carboxylic acid (prepared in step 2) (3.5 g, 20.31 mmol, 1.00 eq.), was placed. N,N-dimethylformamide (50 mL), 4-methoxy-3-[(1-methylpyrrolidin-3-yl)methoxy]aniline (4.8 g, 20.31 mmol, 1.00 eq.), DIEA (5.24 g, 40.62 mmol, 2.00 eq.) and HATU (9.3 g, 24.46 mmol, 1.20 eq.). The resulting solution was allowed to stir at room temperature for 2 h. The crude reaction mixture was filtered and subjected to preparative reverse-phase MPLC purification (Prep-C18, 20-45 pM, 120 g, Tianjin Bonna Agela Technologies; gradient elution of 15-25 % MeCN in water over a period of 10 min, where both solvents contain 0.05% TFA) to give N-[4-methoxy-3-[(1-methylpyrrolidin-3-yl )methoxy]phenyl]-1,4-dioxaspiro[4.4]nonane-6-carboxamide as TFA salt as a yellow oil (3.4 g, 43%). LCMS (ES) [M-TFA+1]+ m/z 390.2.

Stage 6

In a 250 ml round bottom flask, a solution of N-[4-methoxy-3-[(1-methylpyrrolidin-3-yl)methoxy]phenyl]-1,4-dioxaspiro[4.4]nonane-6 -carboxamide (3.4 g, 8.71 mmol, 1.00 eq.), MeCN (50 mL), aqueous HCl solution (17.5 mL, 2.0 N, 34.9 mmol, 4.00 eq.). The resulting solution was allowed to stir at 50 °C for 5 h. The mixture was concentrated under reduced pressure to give crude N-[4-methoxy-3-[(1-methylpyrrolidin-3-yl)methoxy]phenyl]-2-oxocyclopentane-1-carboxamide hydrochloride salt as a yellow oil ( 3.05g, 91%). LCMS (ES) [M+1]+ m/z 347.2.

stage 7

In a 100 mL round bottom flask, a solution of N-[4-methoxy-3-[(1-ethylpyrrolidin-3-yl)methoxy]phenyl]-2-oxocyclopentane-1-carboxamide hydrochloride salt ( 3.05 g, 8.80 mmol, 1.00 eq.), toluene (30 ml), and polyphosphoric acid (3 ml). The resulting mixture was allowed to stir at 100 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was diluted with water (100 ml) and basified with aqueous NaOH solution (2.0 N) to pH ~8. The mixture was extracted with dichloromethane/methanol (10/1) three times. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with ethyl dichloromethane/methanol (8/1) to give 8-methoxy-7-[(1-methylpyrrolidin-3-yl)methoxy]-1H,2H, 3H-cyclopenta[c]quinolin-4-ol as a yellow oil (2.6 g, 90%). LCMS (ES) [M+1]+ m/z 328.2.

Stage 8

In a 100 mL round bottom flask, a solution of 8-methoxy-7-[(1-methylpyrrolidin-3-yl)methoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-ol ( 2.6 g, 7.92 mmol, 1.00 eq.) and POCl3 (30 mL). The resulting solution was allowed to stir at 100 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was diluted with 100 mL of dichloromethane, added dropwise to ice water (100 mL) and basified with aqueous NaOH solution (2.0 N) to pH ~9. The resulting mixture was extracted three times with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with ethyl dichloromethane/methanol (8/1) to give the title product as a pale yellow solid (1.35 g, 49%). LCMS (ES) [M+1]+ m/z 347.1.

Reference 12

Synthesis of 6-chloro-2-methoxy-3-[(1-methylpyrrolidin-3-yl)methoxy]-7,8,9,10-tetrahydrophenanthridine (Intermediate II-6)

The title compound was prepared from 4-methoxy-3-[(1-methylpyrrolidin-3-yl)methoxy]aniline (prepared in the synthesis of Intermediate II-5, Step 4) following the synthetic procedure described for the synthesis of 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate II-1), except that used methyl 2-oxocyclohexane-1-carboxylate instead of methyl 2-oxocyclopentane-1-carboxylate. LCMS (ES) [M+1]+ m/z 361.2.

Reference 13

Synthesis of 1-[3-({4-chloro-6-fluoro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate II-7)

The title compound was prepared as described in Reference 11, Steps 5-8, except that 2-fluoro-4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline (Intermediate Compound I- 6) was used in place of 4-methoxy-3-[(1-methylpyrrolidin-3-yl)methoxy]aniline. LCMS (ES) [M+1]+ m/z 379.2.

Reference 14

Synthesis of 1-[3-({1-benzyl-4-chloro-8-methoxy-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate I II-1)

Stage 1

Lithium diisopropylamide (LDA) (6.3 mL, 2.0 M in THF, 12.6 mmol, 2.20 eq.) dropwise over 5 min. The resulting mixture was allowed to stir at -20 °C under N2 atmosphere for 1.5 h. Dry carbon dioxide gas was passed through this solution at -20 °C for 0.5 h. The reaction was then quenched with saturated aqueous NH4Cl solution (6.3 mL), then diluted with water. The pH was adjusted to 2~3 with concentrated HCl. The resulting solution was extracted three times with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate. The solids were filtered off. The filtrate was concentrated under reduced pressure to give 1-benzyl-2-oxopyrrolidine-3-carboxylic acid as a colorless oil (700mg, 56%). LCMS (ES) [M+1]+ m/z 220.2.

Stage 2

In a 40 ml vial filled with a solution of 1-benzyl-2-oxopyrrolidine-3-carboxylic acid (700 mg, 3.19 mmol, 1.00 eq.) in dichloromethane (15 ml) was added 4-methoxy-3-[3 -(pyrrolidin-1-yl)propoxy]aniline (Intermediate I-2) (839 mg, 3.35 mmol, 1.05 eq.), diisopropylethylamine (825 mg, 6.38 mmol, 2.00 eq.) and HATU (1.46 g, 3.84 mmol , 1.20 eq.). The resulting mixture was allowed to stir at rt for 0.5 h. The solution was diluted with dichloromethane, washed with saturated aqueous NaHCO3. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1-benzyl-N-[4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]phenyl]-2 -oxopyrrolidine-3-carboxamide as a brown oil (1.15 g, 80%). LCMS (ES) [M+1]+ m/z 452.4.

Stage 3

In a 50 ml round bottom flask, a mixture of 1-benzyl-N-[4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]phenyl]-2-oxopyrrolidine-3-carboxamide was placed. (1.15 g, 2.55 mmol, 1.00 eq.) and POCl3 (23 mL). The resulting mixture was allowed to stir at 110 °C under a condenser for 3 h. The reaction was concentrated under reduced pressure and quenched with ice water (20 mL). The pH value of the solution was adjusted to 8 with saturated aqueous NaHCO3. The resulting solution was extracted with a mixed solution of dichloromethane/MeOH (v/v=10/1) three times. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with petroleum ether/THF (5% TEA) (1/4) to give 1-[3-({1-benzyl-4-chloro-8- methoxy-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate III-1) as a brown solid (600 mg, 52%). Lc Ms (ES) [M+1]+ m/z 452.2.

Reference 15

Synthesis of 1-[3-({4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl}oxy)-propyl]pyrrolidine ( Intermediate Compound 111-2)

Stage 1

To a solution of 5,5-dimethylpyrrolidin-2-one (2.0 g, 17.67 mmol, 1.00 eq.) in N,N-dimethylformamide (50 mL) was added sodium hydride (848 mg, 21.20 mmol, 1.20 eq.) in portions at 0 °C. The resulting solution was allowed to stir under N2 atmosphere at 0 °C for 0.5 h. To the above solution was added a solution of p-methoxybenzyl chloride (3.32 g, 21.20 mmol, 1.20 eq.) in N,N-dimethylformamide (10 mL) dropwise over 5 min. The solution was allowed to stir at room temperature for 16 hours before quenching with water. The mixture was extracted three times with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated to reduced pressure. The residue was purified by reverse phase preparative MPLC (Prep-C18, 20-45 ^M, 120 g, Tianjin Bonna-Agela Technologies; gradient elution of 40-60% MeCN in water over a period of 8 min, in in which both solvents contained 0.1% formic acid (FA)) to give 1-[(4-methoxyphenyl)methyl]-5,5-dimethylpyrrolidin-2-one as a yellow oil (2.87 g, 70%). LCMS (ES) [M+1]+m/z 234.1.

Stage 2

Into a 100 mL 3-neck round bottom flask was placed a solution of 1-[(4-methoxyphenyl)-methyl]-5,5-dimethylpyrrolidin-2-one (2.00 g, 8.57 mmol, 1.00 eq.) in dry THF (40 mL). To the above solution, a solution of t-BuLi (12.3 mL, 1.6 M in pentane, 19.7 mmol, 2.3 eq.) was added dropwise with stirring at -78 °C. The resulting solution was allowed to stir for 1.5 hours at -78°C under N2 atmosphere. Dry CO2 gas was passed through the above solution at -78 °C for 0.5 h. After warming to 0°C, the reaction mixture was quenched with saturated aqueous NH4Cl solution and diluted with water. The pH was adjusted to 2~3 with concentrated HCl and then extracted three times with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-[(4-methoxyphenyl)methyl]-5,5-dimethyl-2-oxopyrrolidine-3-carboxylic acid as a colorless oil (2.10 g, 87%). LCMS (ES) [M+1]+ m/z 278.2.

Stage 3

In a 50 mL round bottom flask, a mixture of 1-[(4-methoxyphenyl)methyl]-5,5-dimethyl-2-oxopyrrolidine-3-carboxylic acid (2.10 g, 7.57 mmol, 1.00 eq. ), 4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline (Intermediate I-2) (1.90 g, 7.59 mmol, 1.00 eq.), dichloromethane (30 mL), DIEA ( 1.96 g , 15.17 mmol, 2.00 eq.) and HATU (3.46 g, 9.10 mmol, 1.20 eq.). The resulting solution was allowed to stir at rt for 0.5 h. The solution was diluted with dichloromethane and washed with saturated aqueous NaHCO3 solution. The organic layer was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography with petroleum ether/THF (5% TEA) (1/2) as eluents to to provide N-[4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]phenyl]-1-[(4-methoxyphenyl)methyl]-5,5-dimethyl-2-oxopyrrolidine-3-carboxamide as a brown oil (2.10 g, 54%). Lc Ms (Es ) [M+1]+ m/z 510.2.

Stage 4

In a 100 ml round bottom flask, a mixture of N-[4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]phenyl]-1-[(4-methoxyphenyl)methyl]- 5,5-dimethyl-2-oxopyrrolidine-3-carboxamide (1.50 g, 2.94 mmol, 1.00 eq.) and PoCl3 (30 mL). The resulting solution was allowed to stir under reflux overnight. The solution was concentrated under reduced pressure. Ice water was added to the residue, and the pH value was adjusted to 8 with NaHCO3 (solid). The mixture was extracted with a mixed 10% MeOH/dichloromethane solution (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel with petroleum ether/THF (1/2) (mixed with 5% TEA) to give 1-[3-([4-chloro-8-methoxy-2 ,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl]oxy)propyl]pyrrolidine (Intermediate III-2) as a brown oil (700 mg, 61%). LCMS (ES) [M+1]+ m/z 390.2.

Reference 16

Synthesis of 1-[3-({5-chloro-9-methoxybenzo[h]1,6-naphthyridin-8-yl}oxy)propyl]pyrrolidine (Intermediate III-3)

Stage 1

In a 250 mL 3-necked round bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a mixture of 1-{3-[4-(4,4-dimethyl-1,3,2-dioxaborolan -2-yl)-2-methoxy-5-nitrophenoxy]propyl}pyrrolidine (Intermediate I-5) (2.8 g, 6.89 mmol, 1.00 eq.), 1,4-dioxane (100 mL), 2-chloropyridine- Methyl 3-carboxylate (1.77 g, 10.32 mmol, 1.50 eq.), potassium carbonate (1.9 g, 13.75 mmol, 2.00 eq.), and Pd(PPh3)4 (797 mg, 0.69 mmol, 0.10 eq.). The resulting mixture was allowed to stir at 100 °C under N2 atmosphere for 4 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with 10% MeOH/CH2Cl2 to give 2-[5-methoxy-2-nitro-4-[3-(pyrrolidin-1-yl)propoxy]phenyl] Methyl pyridine-3-carboxylate (1.6 g, 56%) as a gray solid. Lc Ms (ES) [M+1]+ m/z 416.1.

Stage 2

In a 100 mL round bottom flask, a mixture of methyl 2-[5-methoxy-2-nitro-4-[3-(pyrrolidin-1-yl)propoxy]phenyl]pyridine-3 carboxylate (1.3 g, 3.13 mmol, 1.00 eq.), ethanol (50 mL), water (5 mL), iron powder (1.75 g, 31.30 mmol, 10.00 eq.), and NH4Cl (830 mg, 15.52 mmol, 5.00 eq. ). The resulting mixture was allowed to stir at 90 °C for 6 h. The solids were filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with 10-15% MeOH/CH2Cl2 to give 9-methoxy-8-[3-(pyrrolidin-1-yl)propoxy]-5H,6H-benzo[ h]1,6-naphthyridin-5-one as a red solid (780 mg, 71%). LCMS (ES) [M+1]+ m/z 354.1.

Stage 3

In a 50 mL round bottom flask, 9-methoxy-8-[3-(pyrrolidin-1-yl)propoxy]-5H,6H-benzo[h]-1,6-naphthyridin-5-one ( 740 mg, 2.09 mmol, 1.00 eq.) and POCl3 (10 mL). The resulting solution was allowed to stir at 100 °C for 6 h. The resulting mixture was concentrated under reduced pressure. To the residue was added ice water. The pH value of the mixture was adjusted to 7 with Na2CO3 (solid). The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with 10-15% MeOH/dichloromethane to give 1-[3-({5-chloro-9-methoxybenzo[h]-1,6-naphthyridine-8 -yl}oxy)propyl]pyrrolidine (Intermediate III-3) as a pale yellow solid (430 mg, 55%). LCMS (ES) [M+1]+ m/z 372.1.

Reference 17

Synthesis of 1-[3-({5-chloro-9-methoxy-2-methylbenzo[h]1,6-naphthyridin-8-yl}oxy)-propyl]pyrrolidine (Intermediate III-4)

The title compound was prepared following a synthetic procedure similar to that described in Reference 16 above except that methyl 2-chloro-6-methylpyridine-3-carboxylate was used instead of methyl 2-chloropyridine-3-carboxylate. LCMS (ES) [M+1]+ m/z 386.2.

Reference 18

Synthesis of 1-[3-({6-chloro-10-methoxy-1H,2H,3H,4H,5H-azepino[3,2-c]quinolin-9-yl}oxy)propyl]pyrrolidine (Intermediate III - 5)

Stage 1

In a mixture at 0 °C of sodium hydride (7.78 g, 60% in mineral oil, 194.58 mmol, 1.10 eq.) in THF (200 ml) under N2 atmosphere, a solution of azepan-2-one (12.0 g, 106.1 mmol, 1.00 eq.) in THF (100 mL) dropwise over 30 min. The resulting mixture was allowed to stir for 30 min at 0 °C. To this resulting mixture a solution of p-methoxybenzyl chloride (18.2 g, 116.21 mmol, 1.10 eq.) in THF (100 mL) was added dropwise over 20 min. The resulting solution was allowed to stir at room temperature for 3 h and was quenched with water under N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with ethyl acetate/petroleum ether (1/1) to give 1-[(4-methoxyphenyl)methyl]azepan-2-one as a pale yellow oil ( 7.2g, 29%). LCMS (ES) [M+1]+ m/z 234.1.

Stage 2

Into a 500 mL 3-neck round bottom flask was placed a solution of 1-[(4-methoxyphenyl)-methyl]azepan-2-one (7.3 g, 31.29 mmol, 1.00 eq.) in THF (150 mL ). To the resulting solution at -78 °C under N2 atmosphere, lithium diisopropylamide (LDA) (39.2 mL, 2 M, 78.3 mmol, 2.5 eq.) was added dropwise. The resulting solution was allowed to stir at -78 °C for 30 min. To the above solution was added a solution of dimethyl carbonate (5.6 g, 62.6 mmol, 2.0 eq.) in THF (50 mL) at -78 °C. The resulting mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was then quenched with saturated aqueous NH4Cl, extracted twice with 10-15% MeOH/CH2Ch. The combined organic layers were concentrated under reduced pressure. The residue was purified by chromatography flash on silica gel column eluted with ethyl acetate/petroleum ether (1/1) to give methyl 1-[(4-methoxyphenyl)methyl]-2-oxoazepan-3-carboxylate as a yellow oil (6.8 g ), 75%). LCMS (ES) [M+1]+ m/z 292.1.

Stage 3

In a 250 mL round bottom flask, a mixture of methyl 1-[(4-methoxyphenyl)-methyl]-2-oxoazepan-3-carboxylate (6.7 g, 23.00 mmol, 1.00 eq.), methanol ( 100 mL) and sodium hydroxide (2.76 g, 69.00 mmol, 3.00 eq.). The resulting solution was allowed to stir for 3 hours at room temperature. The pH of the reaction mixture was adjusted to ~6 with aqueous HCl (1.0M) and then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with 10% MeOH/dichloromethane to give 1-[(4-methoxyphenyl)methyl]-2-oxoazepan-3-carboxylic acid as a yellow solid (6.1 g , 96%). LCMS (ES) [M+1]+ m/z 278.1.

Stage 4

In a 1 L round bottom flask, a mixture of 1-[(4-methoxyphenyl)methyl]-2-oxoazepan-3-carboxylic acid (6.1 g, 22.00 mmol, 1.00 eq.), CH2Cl2 (300 mL ), 4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline (Intermediate I-2) (6.1 g, 24.13 mmol, 1.10 eq.), N,N-diisopropylethylamine (DIEA) (14.2 g, 109.87 mmol, 5.00 eq.) and HATU (9.2 g, 24.20 mmol, 1.10 eq.). The resulting solution was allowed to stir at rt for 4h. The solution was washed with H2O (2 x 50 mL) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel using 10% MeOH/dichloromethane as eluents to give N-[4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]phenyl]-1- [(4-methoxyphenyl)-methyl]-2-oxoazepan-3-carboxamide as a yellow oil (8.1 g, 72%). LCMS (ES) [M+1]+ m/z 510.3.

Stage 5

In a 100 ml round bottom flask, a solution of N-[4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]phenyl]-1-[(4-methoxyphenyl)methyl]- 2-oxoazepan-3-carboxamide (2.5 g, 4.91 mmol, 1.00 eq.) and POCl3 (30 mL). The resulting solution was allowed to stir at 100 °C for 10 h. The mixture was concentrated under reduced pressure. The residue was diluted with ice water (30 mL). The reaction mixture was treated with potassium carbonate (solid) until pH ~9, and extracted three times with 20% dichloromethane/80% MeOH mixed solution. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with 10-20% MeOH/dichloromethane/methanol (0.1% NH4OH) to give the title compound (Intermediate III-5) as a yellow solid (0.9 g, 47%). LCMS (ES) [M+1]+ m/z 390.2.

Reference 19

Synthesis of 1-[3-({5-chloro-9-methoxy-1H,2H,4H-pyrano[3,4-c]quinolin-8-yl}oxy)-propyl]pyrrolidine (Intermediate III-6)

Stage 1

In a 250 mL round bottom flask, a mixture of methyl 4-oxo-tetrahydro-2H-pyran-3-carboxylate (5.64 g, 35.69 mmol, 1.00 eq.), toluene (100 mL), ethane- 1,2-diol (4.43 g, 71.39 mmol, 2.0 eq.), p-TsOH (615 mg, 3.57 mmol, 0.10 eq.). The resulting mixture was allowed to stir for 24 h with reflux under a Dean Stark trap. The mixture was concentrated and the residue was purified by silica gel column eluted with 20% ethyl acetate/petroleum ether to give methyl 1,4,8-trioxaspiro[4.5]decane-6-carboxylate as a colorless oil (6.7 g, 93%). LCMS (ES) [M+1]+ m/z 203.1.

Stage 2

In a mixture of methyl 1,4,8-trioxaspiro[4.5]decane-6-carboxylate (6.70 g, 33.16 mmol, 1.00 eq.) in MeOH/THF/H2O (50 mL/50 mL/50 mL) NaOH (2.65 g, 66.32 mmol, 2.0 eq.) was added. The resulting solution was allowed to stir at room temperature for 4 h. Organic solvents were removed under reduced pressure. The resulting mixture was acidified to pH 5~6 with aqueous HCl (1.0N), extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to to provide 1,4,8-trioxaspiro[4.5]decane-6-carboxylic acid as a white solid (3.97 g, 64%). LCMS (ES) [M-1]- m/z 187.1.

Stage 3

[The title compound was prepared following a procedure similar to that described above in Reference 11, Steps 5-8 but using 1,4,8-trioxaspiro[4.5]decane-6-carboxylic acid and 4-methoxy-3-[3 -(pyrrolidin-1-yl)propoxy]aniline (Intermediate Compound I-2). The final crude product was purified by flash column chromatography on silica gel eluted with 10% MeOH/CH2Cl2 (0.1% NH4OH) to provide the title compound as a White solid. LCMS (ES) [M+1]+ m/z 377.2.

Reference 20

Synthesis of 1-[3-({4-chloro-8-methoxy-1H,3H-furo[3,4-c]quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate III-7)

The title compound was prepared from 4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline (Intermediate I-2) and ethyl 4-oxotetrahydrofuran-3-carboxylate following similar synthetic sequences. to those described for the synthesis of 8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-ol in Example 37 below and (Compound intermediate II-1 above, except that the final crude product was purified by reverse phase preparative MPLC (Prep-C18, 20-45 ^M, 120 g, Tianjin Bonna-Agela Technologies; 25-45% MeCN gradient elution in water over a period of 12 min, where both solvents contained 0.1% formic acid (FA)) to give the desired 1-[3-({4-chloro-8-methoxy-1H,3H-furo [3,4-c]quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate III-7) as formate salt, LCMS (ES) [M-FA+1]+m/z 363.2.

Reference 21

Synthesis of 8-(benzyloxy)-6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine (Intermediate III-8)

Stage 1

In a 250 mL round bottom flask was placed a solution of 4-(benzyloxy)cyclohexan-1-one (10.0 g, 48.96 mmol, 1.00 eq.) in THF (100 mL). The flask was placed in an ice bath, sodium hydride (2.35 g, 60% dispersion in mineral oil, 58.75 mmol, 1.20 eq.) and dimethyl carbonate (6.62 g, 73.49 mmol, 1.50 eq.) were added to the solution. eq.) in N2 atmosphere. The resulting mixture was left under stirring in an oil bath at 80 °C for 2 h. After the reaction was cooled to room temperature, the reaction mixture was quenched with water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl 5-(benzyloxy)-2-oxocyclohexane-1-carboxylate as a colorless oil (12.5 g, 97%) . LCMS (ES) [M+1]+m/z 263.1.

Stage 2

In a 250 mL round bottom flask was placed a mixture of methyl 5-(benzyloxy)-2-oxo-cyclohexane-1-carboxylate (9.18 g, 35.00 mmol, 1.00 eq.), ethane-1,2-diol (21.7 g, 349.62 mmol, 10.00 eq.), p-TsOH (1.81 g, 10.50 mmol, 0.30 eq.), and toluene (100 mL). The resulting solution was allowed to stir at 125 °C for 16 h with a Dean-Stark trap to remove water. The reaction mixture was allowed to cool to rt and was concentrated under reduced pressure. The remaining residue was diluted with 200 ml of H2O and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide the desired crude product of 8-(benzyloxy)-1,4-dioxaspiro[4.5]decane-6-carboxylate. of methyl as a yellow oil (10.8 g).

Stage 3

In a 250 mL round bottom flask, a solution of methyl 8-(benzyloxy)-1,4-dioxaspiro[4.5]decane-6-carboxylate (5.50 g, 17.95 mmol, 1.00 eq.), was placed. methanol (100 mL), water (10 mL), and sodium hydroxide (3.59 g, 89.75 mmol, 5.00 eq.) in portions. The resulting solution was allowed to stir at 60 °C for 2 h and was then concentrated under reduced pressure. The residue was diluted with 100 ml of H2O. The pH value of the solution was adjusted to 5 with aqueous HCl (2.0 N). The mixture was extracted five times with 10% MeOH/CH2Cl2. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the desired crude product of 8-(benzyloxy)-1,4-dioxaspiro[4.5]decane-6-carboxylic acid as a yellow oil. (4.75g, 91%). LCMS (ES) [M+1]+ m/z 293.1.

Stage 4

In a 250 mL round bottom flask, a mixture of 8-(benzyloxy)-1,4-dioxaspiro-[4.5]decane-6-carboxylic acid (4.50 g, 15.39 mmol, 1.00 eq.), N,N-dimethylformamide (60 mL), 4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline (3.85 g, 15.34 mmol, 1.00 eq.), N,N-diisopropylethylamine (DIEA) ( 5.96 g, 46.12 mmol, 3.00 eq.) and HATU (8.78 g, 23.09 mmol, 1.50 eq.). The mixture was allowed to stir at room temperature for 1.0 h. The resulting mixture was diluted with H2O and extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 8-(benzyloxy)-N-[4-methoxy-3-[3-(pyrrolidin-1-yl )propoxy]phenyl]-1,4-dioxaspiro[4.5]decane-6-carboxamide as a yellow oil (5.13 g, 64%). LCMS (ES) [M+1]+ m/z 525.3.

Stage 5

In a mixture at 0 °C of 8-(benzyloxy)-N-[4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]phenyl]-1,4-dioxaspiro[4.5]decane- 6-carboxamide (5.13 g, 9.78 mmol, 1.00 eq.) in THF (50 mL) was added to aqueous HCl (37%, 15 mL) dropwise over 5 min. The solution was allowed to stir at rt for 0.5 h. Then, the resulting mixture was concentrated under reduced pressure. The residue was diluted with 100 ml of H2O. The pH value of the solution was adjusted to 8 with aqueous NaOH (2.0 N). The resulting mixture was extracted four times with 10% MeOH/CH2Cl2. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 5-(benzyloxy)-N-[4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]phenyl]-2 -oxocyclohexane-1-carboxamide as crude brown oil (4.56 g, 97%). LCMS (ES) [M+1]+ m/z 481.3.

Stage 6

In a 50 mL round bottom flask, a mixture of 5-(benzyloxy)-N-[4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]phenyl]-2-oxocyclohexane-1 -carboxamide (4.56 g, 9.49 mmol, 1.00 eq.) and POCl3 (15 mL). The resulting solution was allowed to stir at 100°C for 2 hours and then concentrated under reduced pressure. To the residue was added 100 ml of ice water. The pH value of the solution was adjusted to 8 with aqueous NaOH (2.0 N), and the mixture was extracted four times with 10% MeOH/CH2Cl2. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give -(benzyloxy)-6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7.8 Crude ,9,10-tetrahydrophenanthridine (Intermediate III-8) as crude brown oil (4.12 g, 90%). LCMS (ES) [M+1]+ m/z 481.2.

Reference 22

Synthesis of 1-[3-({5-chloro-9-methoxy-3-methyl-1H,2H,3H,4H-benzo[c]2,7-naphthyridin-8-yl}oxy)propyl]pyrrolidine (Compound intermediate III-9)

Stage 1

In a -78 °C solution of 1-tert-butyl-3-methyl-4-oxopiperidine-1,3-dicarboxylate (2.0 g, 7.78 mmol, 1.00 eq.), in CH2Cl2 (50 mL) was added N, N-diisopropylethylamine (DIEA) (2.0 g, 15.56 mmol, 2.0 eq.) followed by Tf2O (3.28 g, 11.67 mmol, 1.50 eq.) dropwise. The resulting mixture was allowed to warm to rt and stirred for 3h. The reaction mixture was quenched with H2O and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered off and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with 25% ethyl acetate/petroleum ether to give 1-(tert-butyl)-3-methyl 4-(((trifluoromethyl)-sulfonyl)oxy)-5,6-dihydropyridine-1,3(2H)-dicarboxylate as a yellow oil (2.4 g, 80%). LCMS (ES) [M+1]+ m/z 390.1.

Stage 2

In a 50 ml round bottom flask was placed a mixture of 1-(tert-butyl)-3-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1,3(2H) -dicarboxylate (479 mg, 1.23 mmol, 1.00 eq.), dioxane (8 mL), water (2 mL), 1-{3-[4-(4,4-dimethyl-1,3,2-dioxaborolan-2 -yl)-2-methoxy-5-nitrophenoxy]propyl}pyrrolidine (Intermediate I-5) (500 mg, 1.23 mmol, 1.0 eq.), Pd(PPh3)4 (141 mg, 0.123 mmol, 0.1 eq.) and Na2CO3 (326 mg, 3.07 mmol, 2.5 eq.). The mixture was allowed to stir at reflux under N2 atmosphere overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with 50% ethyl acetate/petroleum ether to give 1-(tert-butyl)-3-methyl-4-(5-methoxy-2-nitro- 4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-5,6-dihydropyridin-1,3(2H)-dicarboxylate as a brown solid (216 mg, 34%). LCMS (Es ) [M+1]+ m/z 520.3.

Stage 3

In a 50 ml round bottom flask, a mixture of 1-(tert-butyl)-3-methyl-4-(5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl) propoxy)phenyl)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (216 mg, 0.415 mmol, 1.00 eq.), MeOH (10 mL), and 10% Pd/C (50 mg). The mixture was degassed and purged with hydrogen. The resulting mixture was allowed to stir under H2 atmosphere at room temperature overnight. The reaction mixture was diluted with MeOH (10 mL) and filtered through a small pad of Celite. The filtrate was concentrated under reduced pressure to give 5-hydroxy-9-methoxy-8-(3-(pyrrolidin-1-yl)propoxy)-1,2-dihydrobenzo[c][2,7]naphthyridine-3(4H tert-butyl )-carboxylate as a brown oil (200 mg, 95%). lCm S (e S) [M+1]+ m/z 458.3.

Stage 4

In a 25 ml round bottom flask was placed 5-hydroxy-9-methoxy-8-(3-(pyrrolidin-1-yl)propoxy)-1,2-dihydrobenzo[c][2,7]naphthyridine-3 (4H)-tert-butyl carboxylate (200 mg, 0.436 mmol, 1.00 eq.) followed by p Oc I3 (10 mL). The resulting solution was allowed to stir at 110 °C for 2 h. Organic volatiles were reduced under reduced pressure. 5 ml of ice/water was added to the residue, and the pH value was adjusted to 8 with Na2CO3 (solid). The precipitate was collected by filtration to yield 5-chloro-9-methoxy-8-(3-(pyrrolidin-1-yl)propoxy)-1,2,3,4-tetrahydrobenzo[c][2,7]naphthyridine ( 180mg, 91%). LCMS (ES) [M+1]+ m/z 376.1.

Stage 5

In a 25 ml round bottom flask, a mixture of 5-chloro-9-methoxy-8-(3-(pyrrolidin-1-yl)propoxy)-1,2,3,4-tetrahydrobenzo[c] [2,7]naphthyridine (180 mg, 0.478 mmol, 1.00 eq.), acetonitrile (5 mL), water (2 mL), CH2O (37% (aq.), 0.2 mL), and NaBH3CN (74.6 mg, 1.18 mmol , 2.5 eq.). The resulting mixture was allowed to stir at rt for 4h. The mixture was filtered and subjected to preparative reverse phase MPLC (Prep-C18, 20-45 ^M, 120 g, Tianjin Bonna-Agela Technologies; gradient elution of 20-40% MeCN in water over a period of 7 min, where both solvents contain 0.1% formic acid (FA) to give the title compound (Intermediate III-9) as the formate salt as a brown solid (110 mg, 59%). LCMS (ES) [M+1]+ m/z 390.3.

Reference 23

Synthesis of 1-[3-({5-chloro-9-methoxy-2,2-dimethyl-1H,2H,3H,4H-benzo[h]1,6-naphthyridin-8-yl}oxy)propyl]pyrrolidine (Intermediate compound III-10)

Stage 1

To a solution of 3-[[(tert-butoxy)carbonyl]amino]-3-methylbutanoic acid (50.0 g, 230.4 mmol, 1.00 eq.) in dichloromethane (1200 mL) was added 2,2-dimethyl-1, 3-dioxane-4,6-dione (33.1 g, 230.4 mmol, 1.00 eq.), EDCI (48.7 g, 253.4 mmol, 1.10 eq.), and 4-dimethylaminopyridine (30.9 g, 253.4 mmol, 1.10 eq.). The resulting solution was allowed to stir at room temperature for 16 h. The solution was washed with H2O (3 x 200 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give 4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5- tert-butyl yl)-2-methyl-4-oxobutan-2-yl-carbamate as an off-white solid (60.5 g, 77%). LCMS (ES) [M-1]- m/z 342.1.

Stage 2

To a solution at 0 °C of N-[4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2-methyl-4-oxobutan-2-yl]carbamate NaBH4 (20.1 g, 528.6 mmol, 3.00 eq.) in portions over 15 min. The resulting solution was stirred at rt for 16h. The mixture was concentrated in vacuo. The residue was subjected to reverse preparative HPLC (Prep-C18, 20-45 jM, 120 g, Tianjin Bonna-Agela Technologies; gradient elution from 40% MeCN in water to 71% MeCN in water over a period of 9 min, where both solvents contain 0.1% TFA) to give 4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2-methylbutan-2-yl-carbamate of tert-butyl as a white solid (35.5 g, 61%). Lc MS (ES) [M-1]-m/z 328.1.

Stage 3

To a solution of tert-butyl N-[4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2-methylbutan-2-yl]carbamate (35.5 g, 107.9 mmol, 1.00 eq.) in methanol (150 ml) was added dioxane (150 ml) which was freshly saturated with hydrochloride (gas). The resulting solution was allowed to stir at room temperature for 16 h. The solution was concentrated in vacuo to give dimethyl 2-(3-amino-3-methylbutyl)malonate hydrochloride as a white solid (23.5 g, 86%). LCMS (ES) [M+1]+ m/z 218.1.

Stage 4

In a 250 mL round bottom flask was placed a solution of methanol (150 mL), 1,3-dimethyl 2-(3-amino-3-methylbutyl)propanedioate hydrochloride (23.5 g, 92.9 mmol, 1.00 eq. .) and TEA (28.1 g, 278.7 mmol, 3.00 eq.). The resulting solution was allowed to stir at 65 °C for 24 h. The volatiles were removed in vacuo. The residue was redissolved with EtOAc (200 mL), washed with brine (2 x 50 mL) and dried over anhydrous sodium sulfate. Removal of organic solvents under reduced pressure gave methyl 6,6-dimethyl-2-oxopiperidine-3-carboxylate as a white solid (20.3 g, crude). LCMS (ES) [m 1]+ m/z 186.2.

Stage 5

To a solution of methyl 6,6-dimethyl-2-oxopiperidine-3-carboxylate (10.0 g, 54.0 mmol 1.00 eq.) in a mixed solution of THF/MeOH/H2O (100 mL, v/v/v = 5 :5:1) lithium hydroxide monohydrate (4.54 g, 108.0 mmol, 2.00 eq.) was added. The resulting mixture was allowed to stir at rt for 16h. The mixture was concentrated in vacuo. The residue was diluted with H2O (20 mL), carefully acidified with aqueous HCl (1.0 N) to pH ~4, and the resulting mixture was extracted with CH2Cl2/MeOH (V/V = 5:1, 3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give 6,6-dimethyl-2-oxopiperidine-3-carboxylic acid as a white solid (7.8 g, 84%). LCMS (ES) [M+1]+ m/z 172.2.

Stage 6

TEA (12.0 g, 116.8 mmol, 2.50 eq.), 4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline (14.0 g, 56.0 mmol, 1.20 eq.), HOBt (9.5 g, 70.0 mmol, 1.50 eq.) and EDCI (13.4 g, 70.0 mmol, 1.50 eq.). The resulting solution was stirred for 16 h at room temperature. The crude reaction mixture was filtered and subjected to reverse preparative HPLC (Prep-C18, 20-45 jM, 120 g, Tianjin Bonna-Agela Technologies; gradient elution from 5% MeCN in water to 30% MeCN in water). water over a period of 7 min, where both solvents contain 0.1% TFA) over several runs to give N-(4-methoxy-3-(3-(pyrrolidin-1-yl)propoxy)phenyl)-6, 6-dimethyl-2-oxopiperidine-3-carboxamide as a white solid (16.8 g, 89%). LCMS (Es ) [M+1]+ m/z 404.2.

Stage 7

In a 250 mL sealed tube, a solution of POCh (100 mL) and N-[4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]phenyl]-6,6-dimethyl-2 -oxopiperidine-3-carboxamide (10.0 g, 24.8 mmol, 1.00 eq.). The resulting solution was stirred at 170 °C for 7 h and then concentrated under reduced pressure. The residue was purified in ice water (50 mL) and carefully basified with aqueous NaOH solution (2.0 N) (pH ~8) and extracted with CH2Ch/MeOH (V/V = 5:1, 3 x 200 mL ). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The crude was diluted with DMF (50 mL), filtered and subjected to reverse preparative HPLC (Prep-C18, 20-45 jM, 120 g, Tianjin Bonna-Agela Technologies; gradient elution of 40% MeCN in water to 71% MeCN in water over a period of 7 min, where both solvents contain 0.1% TFA) over multiple cycles to give the title compound as an off-white solid. The compound was further purified by silica gel column eluted with DCM/MeOH (4/1) to give the title compound as a brown solid (0.5447 g, 5%). 1H NMR (300 MHz, CDaO D^) 87.20 (s, 1H), 6.80 (s, 1H), 4.75 (s, 1H), 4.17 (t, J = 5.9 Hz, 2H), 4.00 (s, 3H) , 3.25 -3.10 (m, 6H), 2.92 (t, J = 6.6 Hz, 2H), 2.39 - 2.33 (m, 2H), 2.07 - 2.02 (m, 5H), 1.83 (t, J = 6.6 Hz, 2H ), 1.37 (s, 6H). LCMS (ES) [M+1]+ m/z 404.2.

Reference 24

Synthesis of 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]piperidine (Intermediate III-11)

The title compound was prepared from 2-methoxy-5-nitrophenol and 1-(3-doropropyl)piperidine hydrochloride following a similar procedure as described above for Intermediate II-1. The crude product was purified by silica gel column eluted with dichloromethane/methanol (10/1) to give the title compound as light brown solid. LCMS (ES) [M+1]+m/z 375.1.

Reference 25

Synthesis of 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]-3,3-dimethylpyrrolidine (Intermediate III-12)

Stage 1

In a 500 mL round bottom flask, a mixture of 2-methoxy-5-nitrophenol (10.0 g, 59.17 mmol, 1.00 eq.), CH3CN (200 mL), 1-chloro-3-iodopropane (18.11 g , 88.76 mmol, 1.50 eq.) and potassium carbonate (16.33 g, 118.34 mmol, 2.00 eq.). The resulting mixture was allowed to stir at 85°C for 3h and cooled to room temperature. The solids were filtered off and the filtrate was concentrated in vacuo. The residue was purified by silica gel column eluted with ethyl acetate/petroleum ether (1/2) to give 2-(3-chloropropoxy)-1-methoxy-4-nitrobenzene as an off-white solid (7.86 g, 54%).

Stage 2

In a 250 mL round bottom flask, a mixture of 2-(3-chloropropoxy)-1-methoxy-4-nitrobenzene (5.0 g, 20.41 mmol, 1.00 eq.), CH3CN (100 mL), hydrochloride 3,3-dimethylpyrrolidine (2.76 g, 20.41 mmol, 1.00 eq.), Cs2Co 3 (13.31 g, 40.82 mmol, 2.00 eq.), and KI (6.78 g, 40.82 mmol, 2.00 eq.). The resulting mixture was allowed to stir for 16 hours at 80°C and cooled to room temperature. The solids were filtered off and the filtrate was concentrated in vacuo. The residue was purified by silica gel column eluted with dichloromethane/methanol (10/1) to give 1-[3-(2-methoxy-5-nitrophenoxy)propyl]-3,3-dimethylpyrrolidine as a yellow solid ( 5.21g, 83%). LCMS (ES) m/z 309.1 [M+1]+.

Stage 3 ~ Stage 6

The title compound was prepared from 1-[3-(2-methoxy-5-nitrophenoxy)propyl]-3,3-dimethylpyrrolidine following a similar procedure as described for the synthesis of Intermediate II-1 above. The crude product was purified by silica gel column eluted with dichloromethane/methanol (10/1) to give the title compound as a yellow solid. LCMS (ES) m/z 389.2 [M+1]+.

Reference 26

Synthesis of [3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]dimethylamine (Intermediate III-13)

The title compound was prepared from 2-methoxy-5-nitrophenol and 3-chloro-N,N-dimethylpropan-1-amine hydrochloride following a similar procedure as described above for the synthesis of Intermediate II-1. The crude product was purified by column chromatography on silica gel eluted with dichloromethane/methanol (10/1) to give the title compound as an off-white solid. 1H NMR (300 MHz, DMSO-de): 7.33 (s, 1H), 7.14 (s, 1H), 4.15 (t, J = 6.0 Hz, 2H), 3.93 (s, 3H), 3.32 - 3.27 (m , 4H), 3.05 (t, J = 6.9 Hz, 2H), 2.44 - 2.39 (m, 2H), 2.18 (s, 6H), 1.96 -1.91 (m, 2H). LCMS (ES) [M+1]+m/z 335.1.

Reference 27

Synthesis of 3-([4-doro-8-methoxy-1H,2H,3H-cydopenta [c]quinolin-7-yl]oxy)propyl]d ie thylam ine (Intermediate compound III-14)

The title compound was prepared from 2-methoxy-5-nitrophenol and 3-doro-N,N-diethylpropan-1-amine following a similar procedure as described above for the synthesis of Intermediate II-1. The crude product was purified by column chromatography on silica gel eluted with dichloromethane/methanol (10/1) to give the title compound as an off-white solid. 1H NMR (300 MHz, DMSO-d6): 7.32 (s, 1H), 7.09 (s, 1H), 4.17 (t, J = 6.0 Hz, 2H), 3.92 (s, 3H), 3.25 (t, J = 7.2 Hz, 2H), 3.02 (t, J = 7.5 Hz, 2H), 2.80 - 2.55 (m, 6H), 2.25 - 2.15 (m, 2H), 2.02 - 1.91 (m, 2H), 1.10 -0.98 ( m, 6H). LCMS (ES) [M+1]+ m/z 363.2.

Reference 28

Synthesis of 4-[3-([4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl]oxy)propyl]morpholine (Intermediate III-15)

The title compound was prepared from 2-methoxy-5-nitrophenol and 4-(3-chloropropyl)morpholine following a procedure similar to that described for the synthesis of Intermediate Compound II-1 above. The crude product was purified by column chromatography on silica gel eluted with dichloromethane/methanol (10/1) to give the title compound as an off-white solid. The crude product was purified by column chromatography on silica gel eluted with dichloromethane/methanol (10/1) to give the title compound as a pale yellow solid. LCMS (ES) [M+1]+m/z 377.2.

Examples 10, 21, 32, 35-38, 40, 52, 56, 70, 75-76, 79-80, 83, 90, 98, 109-111, 113-114, 127-133, 141-148 and 166 fall outside the scope of the claims, but are retained as useful background information.

Example 1

Synthesis of 8-methoxy-N-methyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine formate

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate II -1) and methylamine (2.0 N in THF), following a procedure similar to that described in Example 3 below, except that the crude product was purified by reverse preparative HPLC (Prep-C18 column, OBD 5 ^M, 19 * 250 mm, Waters; gradient elution of 0-40 % MeCN in water over a period of 20 min, where both solvents contain 0.1% formic acid, flow rate: 20 mL/min) to give the title compound as a brown syrup. LCMS (ES) [M+1]+ m/z 356.2.

Example 2

Synthesis of 2-methoxy-N-methyl-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-6-amine formate The title compound was prepared from 6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine (Intermediate II-2) and methylamine (2.0 N in THF), following a procedure similar to that described in Example 3 below, except that the reaction was carried out in a microwave reactor at 80 °C for 2 h. The crude product was purified by reverse preparative HPLC (Prep-C 18, OBD 5 ^M column, 19 * 250 mm, Waters; gradient elution of 0-40 % MeCN in water over a period of 20 min, in which both solvents contain 0.1% formic acid, flow rate: 20 mL/min) to give the title compound as a brown syrup. LCMS (ES) [M+1]+ m/z 370.2.

Example 3

Synthesis of 8-Methoxy-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta-[c]quinolin-4-amine trifluoroacetate

A mixture of 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]-pyrrolidine (Intermediate II-1) (250 mg , 0.69 mmol, 1.00 eq.), 1,4-dioxane (5 mL), and t-BuONa (331 mg, 3.45 mmol, 5.00 eq.) in a microwave reaction vial was purged with N2 for 5 min. Propan-2-amine (285 mg, 4.83 mol, 7.00 eq.) and third-generation BrettPhos precatalyst (64 mg, 0.07 mmol, 0.10 eq.) were added to the solution. After purging with N2 for an additional 2 min, the resulting solution was sealed and subjected to a microwave reactor (120 °C, 1.5 h). The reaction mixture was allowed to cool to rt and quenched with H2O. After removal of volatiles under reduced pressure, the residue was re-dissolved in DMSO, filtered and subjected to preparative reverse cHPL (Prep-C18 column, XBridge 5mM, 19*150mm, Waters; MeCN gradient elution at 10-25% in water over a period of 10 min, with both solvents containing 0.1% trifluoroacetic acid (TFA) to give the title compound as a brown oil (70 mg, 15%).LCMS (ES) [ M+1]+ m/z 384.

Example 4

Synthesis of 2-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)ethan-1-ol trifluoroacetate

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate II -1) and 2-aminoethane-1-ol, following a procedure similar to that described in Example 3 above. The crude product was purified by reverse preparative HPLC (Prep-C18 column, XBridge 5 mM, 19 x 150 mm, Waters; gradient elution of 10-25% MeCN in water over a period of 10 min, in which both solvents contain 0.1% trifluoroacetic acid (TFA)) to give the title compound as a brown oil. LCMS (ES) [M+1]+ m/z 386.3.

Example 5

Synthesis of 8-Methoxy-N-(2-phenylethyl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine trifluoroacetate

1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy) was placed in a 50 mL round bottom flask kept under dry nitrogen. propyl]pyrrolidine (Intermediate II-1) (150 mg, 0.42 mmol, 1.00 eq.), 1,4-dioxane (10 mL), 2-phenylethane-1-amine (103 mg, 0.85 mmol, 2.00 eq.) , Cs2CO3 (277 mg, 0.85 mmol, 2.00 eq.), Pd2(dba)3CHCl3 (43 mg, 0.05 mmol, 0.10 eq.), and subsequently 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl (26 mg, 0.04 mmol, 0.10 eq.). The resulting mixture was allowed to stir at 100 °C under N2 atmosphere overnight. The crude reaction mixture was cooled to rt and treated with water (5 mL). After removal of volatiles, the residue was re-dissolved in DMSO, filtered and subjected to preparative reverse-phase HPLC purification (Prep-C18 column, SunFire 5 ^M, 19*150 mm, Waters; gradient elution). 5-20% MeCN in water for a period of 1 min and MeCN at 20%-43 % in water over a period of 6.5 min, both solvents containing 0.1% trifluoroacetic acid (TFA)) to give the title compound as a yellow semi-solid (102.0 mg, 36%). LCMS (ES) [M+1]+ m/z 446.3.

Example 6

Synthesis of 8-methoxy-2-methyl-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4 formate -amine

In a 50 mL round bottom flask, a mixture of propan-2-amine (248 mg, 4.20 mmol, 2.00 eq.), 1,4-dioxane (20 mL), sodium sulfate (895 mg, 6.30 mmol, 3.00 eq.), tBuONa (604 mg, 6.30 mol, 3.00 eq.), third-generation BrettPhos precatalyst (381 mg, 0.42 mmol, 0.20 eq.), and 1-[3-({4-chloro-8- methoxy-2-methyl-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate II-3) (787 mg, 2.10 mmol, 1.00 eq.). The resulting mixture was allowed to stir at 90 °C under N2 atmosphere for 2 h. The mixture was cooled to room temperature, filtered and subjected to preparative reverse-phase HPLc purification (Prep-C18 column, SunFire 5 ^M, 19 x 150 mm, Waters; gradient elution from 17-34% MeCN in water over a period of 7 min, where both solvents contain 0.1% FA) to give the title compound as a yellow solid (102.8 mg, 12.3%). LCMS (ES) [M+1]+ m/z 398.4.

Example 7

Synthesis of N-cyclobutyl-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine formate

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta-[c]quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate II -1) and cyclobutylamine, following a procedure similar to that described in Example 5 above, except that the reaction solution was allowed to stir at 100 °C under N2 atmosphere for 16 h. The crude product was purified by reverse preparative HPLC (Prep-C18 column, XBridge 5 ^M, 19 x 150 mm, Waters; gradient elution of 8-24% MeCN in water over a period of 7 min, in which both solvents contain 0.1% FA) to give the title compound as an off-white solid (153.8 mg, 19%). LCMS (ES) [M+1]+ m/z 396.4.

Example 8

Synthesis of N-cyclopentyl-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine trifluoroacetate

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate II - 1) and cyclopentylamine, following the procedure described above in Example 3, except that the reaction was carried out in a microwave reactor at 130 °C for 2.5 h. The crude reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with 10% MeOH/CH2Cl2. The desired fractions were combined and concentrated under reduced pressure. The resulting crude product was further purified by preparative HPLC (SunFire Prep-C18 column, 5 ^M XBridge, 19 x 150 mm, Waters; gradient elution of 36-49% MeCN in water over a period of 8 min, at in which both solvents contain 0.05% TFA) to give the title compound as an off-white solid (522.9 mg, 49%). LCMS (ES) [M+1]+ m/z 410.4.

Example 9

Synthesis of 8-Methoxy-N-methyl-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cidopenta[c]quinolin-4 trifluoroacetate -amine

A mixture of 8-methoxy-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cidopenta[c ]quinolin-4-amine (Example 3) (110 mg, 0.29 mmol, 1.00 eq.), ethanol (10 mL), CH2O (37% aqueous) (0.23 mL, 2.90 mmol, 10.00 eq.), and NaBHaCN (54 mg, 0.86 mmol, 3.00 eq.). The resulting solution was allowed to stir at 120 °C for 16 h. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC purification (Prep-C18 column, SunFire 5 ^M, 19*150 mm, Waters; gradient elution of 20-32% MeCN in water over a 9.5 min period, where both solvents contain 0.1% trifluoroacetic acid (TFA) to give the title compound as a yellow solid (18.5 mg, 10%) LCMS (ES) [M+1]+ m/z 398.2.

Example 10

Synthesis of 1-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}pyrrolidine formate

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate II -1) and pyrrolidine, following the procedure described above in Example 3, except that the reaction solution was allowed to stir at 100 °C under N2 atmosphere for 14 h. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC purification (Prep-C18 column, XBridge 5 ^M, 19*150 mm, Waters; gradient elution from 5-22% MeCN in water over a 7 min period, where both solvents contain 0.1% formic acid (FA) to give the title compound as a dark green solid (119.3 mg, 65%). LCMS (ES) [M+1]+ m/z 396.2.

Example 11

Synthesis of 8-Methoxy-7-[(1-methylpyrrolidin-3-yl)methoxy]-N-(propan-2-yl)-1H,2H,3H-cyclopenta[c]quinolin-4-amine trifluoroacetate

3-[({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)methyl]-1-methylpyrrolidine (Intermediate 11- 5) (300 mg, 0.86 mmol, 1.00 eq.), 1,4-dioxane (6 mL), propan-2-amine (255 mg, 4.31 mmol, 5.00 eq.), t-BuONa (165 mg, 1.72 mmol , 2.00 eq.) and subsequently the third BrettPhos precatalyst (78.4 mg, 0.086 mmol, 0.10 eq.). The resulting mixture was purged with N2 for 5 min, sealed and allowed to stir at 90 °C for 2 h. The crude reaction mixture was concentrated under reduced pressure. The remaining residue was re-dissolved in DMSO, filtered and subjected to preparative reverse-phase HPLC purification (Prep-C18 column, XBridge 5 ^M, 19*150 mm, Waters; MeCN gradient elution at 19-24 % in water over 7 min, where both solvents contain 0.1% trifluoroacetic acid (TFA)) to give the title compound as a brown oil (203.1 mg, 39%). LCMS (ES) [M+1]+ m/z 370.4.

Example 12

Synthesis of 2-methoxy-N-(oxan-4-yl)-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-6-amine trifluoroacetate

The title compound was prepared from 6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine (Intermediate 11-2) and tetrahydro - 2H-pyran-4-amine as described above in Example 3. The crude product was purified by reverse preparative HPLC (Prep-C18 column, XBridge 5 mM, 19 x 150 mm, Waters; MeCN 10% gradient elution). -33 % in water over a period of 10 min, where both solvents contain 0.1% trifluoroacetic acid (TFA) to give the title compound as a brown syrup LCMS (ES) [M+1]+ m/z 440.3.

Example 13

Synthesis of 2-methoxy-N-(propan-2-yl)-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-6-amine formate

The title compound was prepared from 6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine (Intermediate II-2) and propan -2-amine following a procedure as described above in Example 3. The crude product was purified by reverse preparative HPLC (Prep-C18 column, XBridge 5 ^M, 19*150 mm, Waters; MeCN 5% gradient elution). -30% in water over a period of 7 min, where both solvents contain 0.1% formic acid (FA) to give the title compound as a brown syrup. LCMS (ES) [M+1]+ m/z 398.3.

Example 14

Synthesis of N-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}acetamide trifluoroacetate

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta-[c]quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate II -1) and acetamide, following a procedure similar to that described in Example 5 above, except that the crude product was purified by reverse preparative HPLC (Prep-C18, 20-45 ^M, 120 g, Tianjin Bonna-Agela Technologies; elution in a gradient of 15-45% MeCN in water over a period of 9 min, where both solvents contain 0.1% trifluoroacetic acid (TFA)) to give the title compound as a brown syrup. LCMS (ES) [M+1]+ m/z 384.2.

Example 15

Synthesis of 2-({2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-6-yl}amino)ethan-1-ol formate

The title compound was prepared from 6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine (Intermediate II-2) and 2 -aminoethane-1-ol, following a procedure similar to that described in the Example 3 above, except that the crude product was purified by reverse preparative HPLC (Prep-C18 column, OBD 5 pM, 19 x 250 mm, Waters; gradient elution of 0-25% MeCN in water over a period of 20 min , where both solvents contain 0.1% formic acid (FA, flow rate: 20 mL/min) to give the title compound as a brown syrup. LCMS (ES) [M+1]+ m/z 400.2.

Example 16

Synthesis of (1r,3r)-3-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino trifluoroacetate )cyclobutan-1-ol

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate II- 1) and trans-3-aminocyclobutan-1-ol, following a similar procedure to that described in Example 3 above, except that the crude product was purified by reverse preparative HPLC (Prep-C18, 20-45 pM, 120 g, Tianjin Bonna-Agela Technologies; gradient elution of 6-31% MeCN in water over a period of 9 min, with both solvents containing 0.1% trifluoroacetic acid (TFA)) to give the title compound as a brown syrup. LCMS (ES) [M+1]+ m/z 412.3.

Example 17

Synthesis of 8-methoxy-N-[(3R)-oxolan-3-yl]-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4 formate -amine

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate II -1) and (R)-tetrahydrofuran-3-amine, following a procedure similar to that described in Example 3, except that the reaction mixture was allowed to stir at 100 °C under a N2 atmosphere for 16 h. The crude product was subjected to preparative reverse phase HPLC (Prep-C18 column, XBridge 5 pM, 19 x 150 mm, Waters; gradient elution of 11-28% MeCN in water over a period of 7 min, in which both solvents contain 0.1% formic acid (FA)) to give the title compound as a pale yellow solid (138.4 mg, 33%). LCMS (ES) [M+1]+ m/z: 412.4.

Example 18

Synthesis of 8-methoxy-N-[(3S)-oxolan-3-yl]-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4 formate -amine

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta-[c]quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate II -1) and (S)-tetrahydrofuran-3-amine, following a procedure similar to that described in Example 3 above, except that the reaction mixture was allowed to stir at 100 °C under a N2 atmosphere for 16 h. The crude product was subjected to preparative reverse phase HPLC (Prep-C18 column, XBridge 5 pM, 19 x 150 mm, Waters; gradient elution of 11-28% MeCN in water over a period of 7 min, in which both solvents contain 0.1% formic acid (FA)) to give the title compound as a brown syrup. LCMS (ES) [M+1]+ m/z 412.4.

Example 19

Synthesis of N-cyclopropyl-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-6-amine formate

The title compound was prepared from 6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine (Intermediate II-2) and cyclopropanamine following a procedure similar to that described in Example 3 above, except that the crude product was purified by reverse preparative HPLC (Prep-C18 column, XBridge 5 ^M, 19 x 150 mm, Waters; MeCN gradient elution at 10-35 % in water over a period of 7 min, where both solvents contain 0.1% formic acid (FA)) to give the title compound as a brown syrup. LCMS (ES) [M+1]+ m/z 396.2.

Example 20

Synthesis of 2-methoxy-6-(methylamino)-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-8-ol formate

The title compound was prepared from 8-(benzyloxy)-6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine (Intermediate 111-8) and methylamine (2.0 M in THF), following a procedure similar to that described in Example 61, except that the crude product was purified by reverse preparative HPLC (Prep-C18 column, OBD 5 ^M, 19 x 250 mm , Waters; gradient elution from 0-40% MeCN in water over a period of 20 min, where both solvents contain 0.1% formic acid, flow rate: 20 mL/min) to give the title compound as a syrup Brown. LCMS (ES) [M+1]+ m/z 386.2.

Example 21

Synthesis of 1-[3-({8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine trifluoroacetate

In a 25 ml round bottom flask, a mixture of 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl] pyrrolidine (Intermediate II-1) (250 mg, 0.69 mmol, 1.00 eq.), N,N-dimethylformamide (10 mL), t-BuONa (331 mg, 3.45 mmol, 5.00 eq.), propan-2-amine (285 g, 4.83 mol, 7.00 eq.), Pd2(dba)3 (321 mg, 0.35 mmol, 0.50 eq.), and PCy3 (26 mg, 0.069 mmol, 0.10 eq.). The resulting solution was allowed to stir for 5 hours at 90 °C under N2 atmosphere. The mixture was filtered and subjected to reverse preparative HPLC (Prep-C18 column, XBridge 5 ^M, 19 x 150 mm, Waters; gradient elution of 8-32% MeCN in water over a period of 7 min, at the that both solvents contain 0.1% trifluoroacetic acid (TFA)) to give the title compound as a brown oil (66.4 mg, 22%). LCMS (ES) [M+1]+ m/z 327.3.

Example 22

Synthesis of 8-Methoxy-N-methyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-pyrrolo[3,2-c]quinolin-4-amine trifluoroacetate Stage 1

In a sealed 8 ml tube under N2 atmosphere, a mixture of 1-[3-({1-benzyl-4-chloro-8-methoxy-1H,2H,3H-pyrrolo[3,2-c]quinoline -7-yl}oxy)propyl]pyrrolidine (Intermediate III-1) (300 mg, 0.66 mmol, 1.00 eq.), 1,4-dioxane (4 mL), MeNH2 (1.6 mL, 2.0 M in THF, 3.32 mmol, 5.00 eq.), t-BuONa (127 mg, 1.32 mmol, 2.00 eq.) and later third-generation BrettPhos precatalyst (30 mg, 0.0332 mmol, 0.05 eq.). The vial was sealed and the solution was allowed to stir at 90°C for 1 hour. The resulting mixture was concentrated and the residue was purified by flash column chromatography on silica gel with 33% petroleum ether in THF (both with 5% trimethylamine) to provide the desired 1-benzyl-8-methoxy- N-methyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-pyrrolo[3,2-c]quinolin-4-amine as a light brown solid. LCMS (ES) [M+1]+ m/z 447.2.

Stage 2

To a solution of 1-benzyl-8-methoxy-N-methyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-pyrrolo[3,2-c]quinolin-4-amine (115 mg, 0.26 mmol, 1.00 eq.) in MeOH (3 mL) and Ch 3C 02H (0.1 mL) was added 10% Pd/C (10 mg). The mixture was degassed and purged with H2 several times. The resulting mixture was allowed to stir at room temperature under an atmosphere of hydrogen for 3 h. The reaction mixture was diluted with MeOH (5 mL), filtered and subjected to preparative reverse-phase HPLC purification (Prep-C18 column, SunFire 5 ^M, 19*150 mm, Waters; MeCN gradient elution at 13-35% in water over a period of 7 min, with both solvents containing 0.1% trifluoroacetic acid (TFA)) to give the title compound as a light brown oil (32.7 mg, 22%). LCMS (ES) [M+1]+ m/z 357.2.

Example 23

Synthesis of 8-Methoxy-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-pyrrolo[3,2c]-quinolin-4-trifluoroacetate amine

The title compound was prepared from 1-[3-({1-benzyl-4-chloro-8-methoxy-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl}oxy) propyl]pyrrolidine (Intermediate III-1), as described in Example 22, Step 1 above, except that propan-2-amine was used instead of methylamine. The crude product was purified by reverse preparative HPLC (Prep-C18 column, SunFire 5 ^M, 19*150 mm, Waters; gradient elution of 5-40% MeCN in water over a period of 7 min, in which both solvents contain 0.1% trifluoroacetic acid (TFA)) to give the title compound as a light brown oil (22.5 mg, 13%). LCMS (ES) [M+1]+ m/z 385.2.

Example 24

Synthesis of 8-Methoxy-N,2,2-trimethyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-pyrrolo[3,2-c]quinolin-4-amine trifluoroacetate

The title compound was prepared from 1-[3-([4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl] oxy)propyl]pyrrolidine (Intermediate 111-2) and methylamine (1.0 N in THF), following a procedure similar to that described in Example 22, Step 1 above, except that the crude reaction mixture was filtered and subjected to purification. on preparative reverse-phase HPLC (Prep-C18 column, SunFire 5 ^M, 19*150 mm, Waters; gradient elution of 15-32% MeCN in water over a period of 7 min, where both solvents contain acid 0.1% trifluoroacetic acid (TFA)) to give the title compound as a brown oil (85.5 mg, 18%). LCMS (ES) [M+1]+ m/z 385.2.

Example 25

Synthesis of 8-Methoxy-2,2-dimethyl-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-pyrrolo[3,2] trifluoroacetate -c]quinolin-4-amine

The title compound was prepared from 1-[3-([4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl] oxy)propM]pyrrolidine (Intermediate III-2) and propan-2-amine, following a procedure similar to that described in Example 22, Step 1 above. The crude reaction mixture was diluted with N,N-dimethylformamide, filtered and subjected to preparative reverse-phase HPLC purification (Prep-C18 column, SunFire 5 ^M, 19 x 150 mm, Waters; MeCN gradient elution 19-35% in water over a period of 7 min, where both solvents contain 0.1% trifluoroacetic acid (TFA)) to give the title compound as a brown oil (118.1 mg, 24%). LCMS (ES) [M+1]+ m/z 413.2.

Example 26

Synthesis of 9-methoxy-N-methyl-8-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H,4H-benzo[h]1,6-naphthyridin-5-amine formate

Stage 1

In a 40 ml sealed tube kept under an inert atmosphere of nitrogen, a mixture of 1-[3-({5-chloro-9-methoxybenzo[h]1,6-naphthyridin-8-yl}oxy)propyl] was added. pyrrolidine (Intermediate 111-3) (210 mg, 0.56 mmol, 1.00 eq.), Cs2CO3 (368 mg, 1.13 mmol, 2.00 eq.), 1,4-dioxane (10 mL), MeNH2/THF (1M in THF , 1.7 mL, 1.68 mmol, 3.00 eq.), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (35 mg, 0.06 mmol, 0.10 eq.), Pd2(dba)3CHCl3 (59 mg, 0.06 mmol, 0.10 eq.). The resulting mixture was allowed to stir at 100 °C under N2 atmosphere for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluted with 10-20% MeOH/CH2Cl2 to give the desired product of 9-methoxy-N-methyl-8-[3- (pyrrolidin-1-yl)propoxy]benzo[h]1,6-naphthyridine-5-amine as a yellow oil (116 mg, 56%). LCMS (ES) [M+1]+ m/z 367.2.

Stage 2

In a 50 ml round bottom flask, a mixture of 9-methoxy-N-methyl-8-[3-(pyrrolidin-1-yl)propoxy]benzo[h]1,6-naphthyridin-5-amine was placed. (111 mg, 0.30 mmol, 1.00 eq.), methanol (10 mL), and 10% Pd/C (50 mg). The mixture was degassed and purged with hydrogen three times. The resulting mixture was allowed to stir at rt for 6h. The mixture was diluted with MeOH (50 mL) and the solids were filtered off through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (5 mL), filtered and subjected to preparative reverse-phase HPLC purification (Prep-C18 column, XBridge 5 ^M, 19 x 150 mm, Waters; gradient elution). 5% MeCN in water over 1.5 min and 5-20% MeCN in water over 7 min, both solvents containing 0.1% formic acid (FA)) to give the title compound as a light yellow solid (57.1 mg, 41%). LCMS (ES) [M+1]+ m/z 371.1.

Example 27

Synthesis of 9-Methoxy-N-(propan-2-yl)-8-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H,4H-benzo[h]1,6-naphthyridine trifluoroacetate -5-amine

The title compound was prepared from 1-[3-({5-chloro-9-methoxybenzo[h]1,6-naphthyridin-8-yl}oxy)propyl]pyrrolidine (Intermediate 111-3) following a procedure similar to that described above in Example 26, except that propan-2-amine was used in place of methylamine in Step 1. The final crude product was purified by reverse preparative HPLC (Prep-C18 column, SunFire 5 ^M, 19 x 150 mm, Waters, 5% MeCN gradient elution in water over 1 min and 5-25% MeCN in water over 7 min where both solvents contain 0.1% trifluoroacetic acid (TFA)) to give the title compound as a yellow oil. LCMS (ES) [M+1]+ m/z 399.2.

Example 28

Synthesis of 1-[3-({9-methoxy-5-methyl-1H,2H,3H,4H-benzo[h]1,6-naphthyridin-8-yl}oxy)propyl]pyrrolidine trifluoroacetate

Stage 1

In a 50 mL 3-neck round bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a mixture of 1-[3-({5-chloro-9-methoxybenzo[h]1,6-naphthyridine -8-yl}oxy)-propyl]pyrrolidine (Intermediate III-3) (220 mg, 0.59 mmol, 1.00 eq.), 1,4-dioxane (20 mL), trimethyl-1,3,5,2, 4,6-trioxatriborinan (598 mg, 50%/W in THF, 2.37 mmol, 4.00 eq.), Cs2CO3 (580 mg, 1.78 mmol, 3.00 eq.), then Pd(PPh3)4 (69 mg, 0.06 mmol, 0.10 eq.). The resulting mixture was left at 110 °C under N2 atmosphere for 3 h and then concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and subjected to purification by flash column chromatography on silica gel eluted with 10-15% MeOH/CH2Cl2 to give the desired product of 1-[3-([9-methoxy- 5-methylbenzo[h]1,6-naphthyridin-8-yl]oxy)propyl]pyrrolidine as a yellow solid (155mg, 75%). LCMS (Es ) [M+1]+ m/z 352.2.

Stage 2

In a 50 mL round bottom flask, a solution of 1-[3-([9-methoxy-5-methylbenzo[h]1,6-naphthyridin-8-yl]oxy)propyl]pyrrolidine (150 mg , 0.43 mmol, 1.00 eq.), methanol (10 mL), 10% Pd/C (15 mg). The mixture was degassed and purged with H2 several times and then stirred at room temperature under H2 (balloon) for 4 h. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC purification (Prep-C18 column, SunFire 5 ^M, 19*150 mm, Waters; gradient elution of 12-25% MeCN in water over a 8 min period, where both solvents contain 0.1% trifluoroacetic acid (TFA)) to give the title compound as a yellow oil (20.4 mg, 8%). LCMS (ES) [M+1]+ m/z 356.2.

Example 29

Synthesis of 9-methoxy-N,2-dimethyl-8-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H,4H-benzo[h]1,6-naphthyridin-5-amine formate

Stage 1

A solution of 1-[3-({5-chloro-9-methoxy-2-methylbenzo[h]1,6-naphthyridin-8-yl}oxy)propyl]pyrrolidine (Intermediate 111- 4) (200 mg, 0.52 mmol, 1.00 eq.), DMSO (10 mL), and CH3NH2 (5.2 mL, 1 M in t Hf , 5.2 mmol, 10.00 eq.). The resulting solution was sealed and allowed to stir at 120°C overnight. The reaction solution was diluted with water and extracted with a 20% MeOH/CH2Cl2 mixed solution. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with 5-20% MeOH/CH2Cl2 to give the desired product of 9-methoxy-N,2-dimethyl-8-[3-(pyrrolidin-1-yl )propoxy]benzo[h]1,6-naphthyridine-5-amine as a yellow solid (125 mg, 63%). LCMS (ES) [M+1]+ m/z 381.3.

Stage 2

In a 50 ml round bottom flask, a solution of 9-methoxy-N,2-dimethyl-8-[3-(pyrrolidin-1-yl)propoxy]benzo[h]1,6-naphthyridine-5 -amine (125 mg, 0.33 mmol, 1.00 eq.), methanol (10 mL), and 10% Pd/C (15 mg). The resulting mixture was degassed and purged with H2 for several hours and allowed to stir at room temperature under H2 for 6 h. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC purification (Prep-C18 column, XBridge 5 ^M, 19*150 mm, Waters; 5-17% MeCN gradient elution in water over a period of 7 min, where both solvents contain 0.1% formic acid (FA) to give the title compound as a white solid (23.3 mg, 16%).LCMS (ES) [M+1 ]+ m/z 385.3.

Example 30

Synthesis of 9-methoxy-2-methyl-N-(propan-2-yl)-8-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H,4H-benzo[h]1 formate ,6-naphthyridine-5-amine

The title compound was prepared from 1-[3-(15-chloro-9-methoxy-2-methylbenzo[h]1,6-naphthyridin-8-yl}oxy)propyl]pyrrolidine (Intermediate III-4 ), following the procedure described in Example 29 above, except that propan-2-amine was used instead of methylamine. The final crude product was purified by reverse preparative HPLC (Prep-C18 column, XBridge 5 ^M, 19 x 150 mm, Waters; gradient elution of 5-25% MeCN in water over a period of 7.5 min, in which both solvents contain 0.1% formic acid (FA)) to give the title compound as a white solid (33.1 mg, 24%). LCMS (ES) [M+1]+ m/z 413.3.

Example 31

Synthesis of 1-[3-({9-methoxy-2,5-dimethyl-1H,2H,3H,4H-benzo[h]1,6-naphthyridin-8-yl}oxy)propyl]pyrrolidine trifluoroacetate

The title compound was prepared from 1-[3-(15-chloro-9-methoxy-2-methylbenzo[h]1,6-naphthyridin-8-yl}oxy)propyl]pyrrolidine (Intermediate 111-4 ), following a procedure similar to that described in example 28 above. The final crude product was purified by reverse preparative HPLC (Prep-C18 column, SunFire 5 ^M, 19 x 150 mm, Waters; gradient elution of 5-35% MeCN in water over a period of 7 min, in which both solvents contain 0.1% trifluoroacetic acid (TFA) to give the title compound as a yellow semi-solid (31.4 mg, 17%). LCMS (ES) [M+1]+ m/z 370.2.

Example 32

Synthesis of 1-[3-({5-cyclopropyl-9-methoxy-2-methyl-1H,2H,3H,4H-benzo[h]1,6-naphthyridin-8-yl}oxy)propyl]pyrrolidine trifluoroacetate

Stage 1

In a 50 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, 1-[3-(15-chloro-9-methoxy-2-methylbenzo[h]1,6-naphthyridin-8-yl }oxy)propyl]-pyrrolidine (Intermediate 111-4) (210 mg, 0.54 mmol, 1.00 eq.), 1,4-dioxane (20 mL), cyclopropylboronic acid (94 mg, 1.09 mmol, 2.00 eq.), Cs2CO3 (356 mg, 1.09 mmol, 2.00 eq.) and later Pd(PPh3)4 (63 mg, 0.05 mmol, 0.10 eq.). The resulting mixture was allowed to stir at 110°C under N2 atmosphere for 4 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with 5-20% MeOH/CH2Cl2 to give the desired product of 1-[3-([5-cyclopropyl-9-methoxy-2-methylbenzo[h] 1,6-naphthyridin-8-yl]oxy)propyl]pyrrolidine as a yellow solid (135mg, 63%). LCMS (ES) [M+1]+ m/z 392.2.

Stage 2

In a rt solution of 1-[3-([5-cidopropyl-9-methoxy-2-methylbenzo[h]1,6-naphthyridin-8-yl]oxy)propyl]pyrrolidine (95 mg, 0.24 mmol, 1.00 eq.) in 1,4-dioxane (5 ml) was added a solution of 1,4-dioxane (1 ml) saturated with HCl (gas). The resulting solution was allowed to stir at room temperature for 1 h and was then concentrated under reduced pressure to provide the corresponding 1-[3-([5-cyclopropyl-9-methoxy-2-methylbenzo[h]1,6 HCl salt -naphthyridin-8-yl]oxy)propyl]pyrrolidine. A solution of the above sa1HCl in methanol (10 mL) and 10% Pd/C (10 mg) was placed in a 50 mL round bottom flask. The resulting mixture was degassed and purged with H2 several times and then allowed to stir at room temperature under H2 for 6 h. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC purification (Prep-C18 column, SunFire 5 ^M, 19 x 150 mm, Waters; gradient elution from 20-33% MeCN in water over a period of 7.5 min, where both solvents contain 0.1% trifluoroacetic acid (TFA)) to give the title compound as a dark yellow solid. LCMS (ES) [M+1]+ m/z 396.2.

Example 33

Synthesis of 10-methoxy-N-methyl-9-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H,4H,5H-azepino[3,2-c]quinolin-6-amine formate

The title compound was prepared from 1-[3-({6-chloro-10-methoxy-1H,2H,3H,4H,5H-azepino[3,2-c]quinolin-9-yl}oxy) propyl]pyrrolidine (Intermediate 111-5) and methylamine (1.0 N in THF), following a procedure similar to that described in Example 22, Step 1. The crude mixture was filtered and subjected to preparative reverse-phase HPLC purification ( Prep-C18 column, 5 ^M XBridge, 19 x 150 mm, Waters, gradient elution of 5-17% MeCN in water over a period of 7 min, both solvents containing 0.1 formic acid (FA) %) to give the title compound as a gray solid LCMS (ES) [M+1]+ m/z 385.2.

Example 34

Synthesis of 10-methoxy-N-(propan-2-yl)-9-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H,4H,5H-azepino[3,2-c] formate ]quinolin-6-amine

The title compound was prepared from 1-[3-({6-chloro-10-methoxy-1H,2H,3H,4H,5H-azepino[3,2-c]quinolin-9-yl}oxy) propyl]pyrrolidine (Intermediate 111-5) following a procedure similar to that described in Example 22, Step 1, except that propan-2-amine was used instead of methylamine. The crude mixture was filtered and subjected to preparative reverse-phase HPLC purification (Prep-C18 column, XBridge 5 ^M, 19 x 150 mm, Waters; gradient elution from 5-21% MeCN in water over a period of 7 min, where both solvents contain 0.1% formic acid (FA)) to give the title compound as a gray solid. LCMS (ES) [M+1]+ m/z 413.3.

Example 35

Synthesis of 1-[3-(18-methoxy-2,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl}oxy)propyl]pyrrolidine formate

To a mixture of 1-[3-([4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl]oxy)propyl]pyrrolidine (Intermediate 111-2) (80.00 mg, 0.21 mmol) and zinc (300 mg, 4.6 mmol, 22 eq.) in MeOH were added with aqueous HCl (37%, 0.5 mL). The mixture was allowed to stir at rt for 72 h and filtered through a small pad of Celite. After removal of solvents under reduced pressure, the residue was filtered and purified by reverse preparative HPLC (Prep-C18 column, 5 pM OBD, 19 x 250 mm, Waters; gradient elution from 0-40% MeCN in water over a period of 20 min, where both solvents contain 0.1% formic acid, flow rate: 20 mL/min) to give the title compound as a brown solid. LCMS (ES) [M+1]+ m/z 356.2.

Example 36

Synthesis of 1-[3-({4-cyclopropyl-8-methoxy-2,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl}oxy)propyl]pyrrolidine formate

A mixture of 1-[3-({4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl}oxy)propyl]pyrrolidine ( Intermediate 111-2) (80.00 mg, 0.21 mmol, 1.00 eq.), cyclopropylboronic acid (44.06 mg, 0.51 mmol, 2.50 eq.), and K2CO3 (87 mg, 0.63 mmol, 3.0 eq.) in a mixed solvent of N,N-dimethylformamide (2.5 mL) and water (1.0 mL) in a sealed vial was purged with N2 for 10 min. To the resulting mixture Pd2(dba)3 (62 mg, 0.067 mmol, 0.32 eq.) was added. The vial was sealed and the mixture was allowed to stir at 100 °C for 3 h. The crude reaction mixture was cooled to rt, quenched with water, and extracted with 30% PrOH/chloroform. The organic layers were combined and concentrated under reduced pressure. The residue was dissolved in DMSO and subjected to purification by reverse preparative HPLC (Prep-C18 column, 5 pM OBD, 19 x 250 mm, Waters; gradient elution from 0-40% MeCN in water over a period of 20 min, where both solvents contain 0.1% formic acid, flow rate: 20 mL/min) to give the title compound as a brown solid. LCMS (ES) [M+1]+ m/z 396.4.

Example 37

Synthesis of 8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-ol trifluoroacetate

In a 50 mL round bottom flask, a mixture of 4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline (Intermediate I-2) (1.00 g, 3.99 mmol, 1.00 eq. .), ethyl 2-oxocyclopentane-1-carboxylate (655 mg, 4.19 mmol, 1.05 eq.), p-TsOH (69 mg, 0.20 mmol, 0.05 eq.), and toluene (15 mL). The resulting mixture was allowed to stir at 110 °C for 1 h. After the starting material was completely consumed, the mixture was cooled to rt. Polyphosphoric acid (1 ml) was added to the mixture. The mixture was allowed to stir at 100 °C for 1.0 h. After removing volatiles under reduced pressure, the residue was diluted with 100 ml of H2O, and the pH value of the solution was adjusted to 9 with aqueous NaOH solution (2N). The mixture was extracted with a solvent mixture of 20% PrOH/80% CHCl3. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to reverse preparative HPLC purification (Prep-C18 column, XBridge 5 pM, 19 x 150 mm, Waters; gradient elution of 17-32% MeCN in water over 7 min, where both solvents contain acid). 0.1% trifluoroacetic acid (TFA), flow rate: 20 mL/min, detector UV wavelength: 254 nm) to give the title compound as a gray solid. LCMS (ES) [M+1]+ m/z 343.2.

Example 38

Synthesis of 2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-6-ol trifluoroacetate

The title compound was prepared from 4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline (Intermediate Compound I-2) following a procedure similar to that described in Example 37, except that ethyl 2-oxocyclohexane-1-carboxylate instead of ethyl 2-oxocyclopentane-1-carboxylate. LCMS (ES) [M+1]+ m/z 375.2.

Example 39

Synthesis of 2-methoxy-N-[1-(propan-2-yl)piperidin-4-yl]-3-[3-(pyrrolidin-1-M)propoxy]-7,8,9,10- trifluoroacetate tetrahydrophenanthridine-6 amine

The title compound was prepared from 6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine (Intermediate II-2) and 1 -isopropylpiperidin-4-amine, following a procedure described in Example 3, except that the crude product was purified by reverse preparative HPLC (Prep-C18 column, SunFire 5 ^M, 19 x 150 mm, Waters; MeCN gradient elution 10-30% in water over a period of 7.5 min, where both solvents contain 0.1% trifluoroacetic acid (TFA) to give the title compound as a brown solid LCMS (ES) [M+1]+m /z 481.4.

Example 40

Synthesis of 2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine trifluoroacetate

The title compound was prepared from 6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine (Intermediate 11-2) following a procedure similar to that described in Example 21. The crude product was purified by reverse HPLC (Prep-C18 column, XBridge 5 ^M, 19 x 150 mm, Waters; gradient elution of 8-32% MeCN in water over a period 7 min, where both solvents contain 0.1% trifluoroacetic acid (TFA)) to give the title compounds as a light brown oil. LCMS (ES) [M+1]+ m/z 341.3.

Example 41

Synthesis of N-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}-1-methylpiperidin-4-amine formate

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate II -1) and 1-methylpiperidin-4-amine, following a procedure similar to that described in Example 3, except that the crude product was purified by reverse preparative HPLC (Prep-C18 column, OBD 5 ^M, 19 x 250 mm, Waters; gradient elution of 0-40% MeCN in water over a period of 20 min, where both solvents contain 0.1% formic acid, flow rate: 20 mL/min) to give the title compound as a white solid . LCMS (ES) [M+1]+ m/z 439.4.

Example 42

Synthesis of 2-methoxy-N-(oxan-4-yl)-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-6-amine formate

The title compound was prepared from 6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine (Intermediate II-2) and tetrahydro -2H-pyran-4-amine, following a procedure similar to that described in Example 3. The crude product was purified by reverse preparative HPLC (Prep-C18 column, OBD 5 pM, 19*250 mm, Waters; gradient elution from 0-MeCN 40 % in water over a period of 20 min, where both solvents contain 0.1% formic acid, flow rate: 20 mL/min) to give the title compound as a white solid. LCMS (ES) [M+1]+ m/z 440.3.

Example 43

Synthesis of N-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}-1-(propan-2- il) piperidine-4-amine

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate II -1) and 1-isopropylpiperidin-4-amine following a procedure similar to that described in Example 3. The crude product was purified by reverse preparative HPLC (Prep-C18 column, OBD 5 pM, 19*250 mm, Waters; elution in gradient of 0-40% MeCN in water over a period of 20 min, where both solvents contain 0.1% formic acid, flow rate: 20 mL/min) to give the title compound as a white solid. LCMS (ES) [M+1]+ m/z 467.4.

Example 44

Synthesis of 8-methoxy-N-(oxetan-3-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine formate

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta-[c]quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate II -1) and oxetan-3-amine, following a procedure similar to that described above in Example 3. The crude product was purified by reverse preparative HPLC (Prep-C18 column, OBD 5 pM, 19*250 mm, Waters; elution at gradient of 5-38% MeCN in water over a period of 20 min, where both solvents contain 0.1% formic acid, flow rate: 20 mL/min) to give the title compound as a brown solid. LCMS (ES) [M+1]+ m/z 398.3.

Examples 45 and 46

Synthesis of 7-methoxy-N-(propan-2-yl)-8-[3-(pyrrolidin-1-yl)propoxy]-1H,3H-furo[3,4-c]quinolin-4-amine (45 ) and 8-methoxy-N-(propan-2-yl)-7-[3-(pyrrolidin-1 -yl)propoxy]-1H,3H-furo[3,4-c]quinolin-4-amine (46 )

Stage 1

In a 250 mL round bottom flask, a solution of 3,4-dimethoxybenzenamine (7.5 g, 48.96 mmol, 1.00 eq.), toluene (100 mL), ethyl 4-oxo-tetrahydrofuran-3-carboxylate ( 9.3 g, 58.75 mmol, 1.20 eq.) and subsequently p-TsOH.H2O (932 mg, 4.90 mmol, 0.1 eq.). The resulting mixture was allowed to stir under Dean-Stark reflux for 4 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium carbonate and brine, and dried over anhydrous sodium sulfate. After removing organic solvents under reduced pressure, the resulting brown solid was dissolved in toluene. Polyphosphoric acid (PPA) (20 mL) was added to the solution. The resulting mixture was stirred at 100 °C for 4 h and then concentrated under reduced pressure. The residue was diluted with water and the pH value of the solution was adjusted to 7 with saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 7,8-dimethoxy-1,3-dihydrofuro[3,4-c]quinolin-4-ol as a compound. thick brown oil (7.1 g). LCMS (ES) [M+1]+ m/z 248.1.

Stage 2

In a 250 mL round bottom flask charged with crude 7,8-dimethoxy-1,3-dihydrofuro[3,4-c]quinolin-4-ol (7.1 g, crude, 28.72 mmol, 1.00 eq.) added POCl3 (100 mL). The resulting solution was allowed to stir at 100 °C for 4 h. After removing volatiles under reduced pressure, the residue was treated with ice/water and the pH value of the solution was adjusted to 7 with aqueous NaHCO3 solution (1.0 M). The resulting mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with ethyl acetate/petroleum ether (1/2) to give 4-chloro-7,8-dimethoxy-1,3-dihydrofuro[3,4-c] quinoline as a yellow solid (3.5 g, 27%, 2 steps). Lc MS (ES) [M+1 ]+ m/z 266.1.

Stage 3

In a 100 mL round bottom flask, a mixture of 4-chloro-7,8-dimethoxy-1,3-dihydrofuro[3,4-c]quinoline (3.5 g, 13.17 mmol, 1.00 eq.), dichloroethane (50 mL) and AlCh (1.75 g, 13.17 mmol, 1.0 eq.). The resulting mixture was allowed to stir at 40 °C for 6 h, cooled to rt, diluted with CH2Cl2, then treated with ice water. The mixture was filtered through a pad of Celite and the filter cake washed with CH2Cl2. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluted with 5% MeOH/CH2Ch to give a mixture of 4-chloro-8-methoxy-7-(3-(pyrrolidin- 1-yl)propoxy)-1,3-dihydrofuro[3,4-c]quinolone and 4-chloro-7-methoxy-8-(3-(pyrrolidin-1-yl)propoxy)-1,3-dihydrofuro[ 3,4-c]quinolone (1:1) as a yellow oil (1.40 g). LCMS (ES) [M+1]+ m/z 252.1.

Stage 4

In a 50 ml round bottom flask, a mixture of 4-chloro-8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-1,3-dihydrofuro[3,4-c] quinolone and 4-chloro-7-methoxy-8-(3-(pyrrolidin-1-yl)propoxy)-1,3-dihydrofuro[3,4-c]quinolone (1:1, 1.40 g, 5.56 mmol, 1.00 eq.), potassium carbonate (2.30 g, 16.69 mmol, 3.0 eq.), acetonitrile (30 mL), 3-(pyrrolidin-1 -yl)propan-1-ol hydrochloride (1.84 g, 10.01 mmol, 1.80 eq. .) and potassium iodide (1.66 g, 10.01 mmol, 1.80 eq.). The resulting mixture was allowed to stir at 80 °C for 3 h. The solids were filtered off and the filter cake washed with acetonitrile (2 x 30 mL). The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography on silica gel eluted with 10% MeOH/CH2Cl2 to give a mixture of 1-[3-({4-chloro-8-methoxy- 1H,3H -furo[3,4-c]quinolin-7-yl}oxy)propyl]pyrrolidine and 1-[3-({4-chloro-7-methoxy-1H,3H-furo[3,4-c ]quinolin-8-yl}oxy)propyl]pyrrolidine (1:1, 0.99 g) as a brown solid. LCMS (ES) [M+1]+ m/z 363.2.

Stage 5

In a sealed 8 mL tube, 1-[3-({4-chloro-8-methoxy-1H,3H-furo[3,4-c]quinolin-7-yl}oxy)propyl]pyrrolidine and 1- [3-({4-chloro-7-methoxy-1H,3H-furo[3,4-c]quinolin-8-yl}oxy)propyl]pyrrolidine (1:1, 330 mg, 0.91 mmol, 1.0 eq. ), dry 1,4-dioxane (4 mL), propan-2-amine (269 mg, 4.56 mmol, 5.00 eq.), t-BuONa (175 mg, 1.82 mmol, 2.00 eq.), 4Á MS (50 mg) and subsequently third-generation BrettPhos precatalyst (56 mg, 0.063 mmol, 0.05 eq.). The resulting mixture was allowed to stir at 90 °C under N2 atmosphere for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column eluted with 10% MeOH/CH2Cl2 to give a mixture of the two desired crude products (326 mg). Purification of this crude mixture by chiral preparative HPLC with the conditions (Phenomenex Lux Cellulose-4 column, 21.2 * 250 mm; Mobile phase: 70% n-Hexane (0.1% diethylamine)/30% Ethanol; flow rate: 20 ml /min; detector 254 nm) to provide two fractions as shown below:

The first fraction was collected (Rt = 6.5 min) to give 7-methoxy-N-(propan-2-yl)-8-[3-(pyrrolidin-1-yl)propoxy]-1H,3H-furo[3, 4-c]quinolin-4-amine (45) as a pale yellow solid (82.5 mg). Lc MS (Es ) [M+1 ]+ m/z 386.3.

The second fraction was collected (R t = 7.2 min) to give 8-m ethoxy-N -(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H, 3H-furo[3,4-c]quinolin-4-am ine (46) as a light yellow solid. LCMS (ES) [M+1]+ m/z 386.4.

Examples 47 and 48

Synthesis of N-cyclopropyl-7-methoxy-8-[3-(pyrrolidin-1-yl)propoxy]-1H,3H-furo[3,4-c]quinolin-4-amine (47) and N-cyclopropyl- 8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-lH,3H-iuro[3,4-c]quinolin-4-amine (48)

The title compounds were prepared from a mixture of 1-[3-({4-chloro-8-methoxy-1H,3H-furo[3,4-c]quinolin-7-yl}oxy)propyl]pyrrolidine and 1-[3-({4-chloro-7-methoxy-1H,3H-furo[3,4-c]quinolin-8-yl}oxy)propyl]pyrrolidine (1:1) (prepared in Example 45 and 46, Step 4), following a procedure similar to that described above in Examples 45 and 46, Step 5, except that cyclopropanamine was used instead of propan-2-amine.

The crude mixture was purified by silica gel column eluted with 10% MeOH/CH2Cl2 to give a mixture containing the two desired products. Purification of this crude mixture by chiral preparative HPLC with the conditions (Phenomenex Lux Cellulose-4 column, 21.2 x 250 mm; Mobile phase: 70% n-Hexane (0.1% diethylamine)/30% Ethanol; flow rate: 20 ml /min; detector 254 nm) to provide two fractions as shown below:

The first fraction was collected (Rt = 15.0 min) to give N-cyclopropyl-7-methoxy-8-[3-(pyrrolidin-1-yl)propoxy]-1H,3H-furo[3,4-c]quinolin- 4-amine (47) as a pale yellow solid (82.5 mg). LCMS (ES) [M+1]+ m/z 384.3.

The second fraction was collected (Rt = 17.8 min) to give N-cyclopropyl-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,3H-furo[3,4-c ] quinolin-4-amine (48) as a pale yellow solid. LCMS (ES) [M+1]+ m/z 384.3.

Example 49

Synthesis of N-(cyclobutylmethyl)-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine formate

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate II- 1) and cyclobutyl methanamine, following a procedure similar to that described above in Example 3. The crude product was purified by reverse preparative HPLC (Prep-C18 column, OBD 5 ^M, 19 x 250 mm, Waters; MeCN gradient elution 0-35% in water over a period of 20 min, where both solvents contain 0.1% formic acid, flow rate: 20 mL/min) to give the title compound as a brown solid. LCMS (ES) [M+1]+ m/z 410.3.

Example 50

Synthesis of 9-methoxy-N-(propan-2-yl)-8-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,4H-pyrano[3,4-c]quinolin-5 formate -amine

The title compound was prepared from 1-[3-({5-chloro-9-methoxy-1H,2H,4H-pyrano[3,4-c]quinolin-8-yl}oxy)propyl]pyrrolidine ( Intermediate 111-6) and propan-2-amine, following a procedure similar to that described above in Example 3 except that the reaction was carried out in a microwave reactor at 80 °C for 3 h. The crude product was purified by reverse preparative HPLC (Prep-C18 column, XBridge 5 ^M, 19 x 150 mm, Waters; gradient elution of 13-35% MeCN in water over a period of 7 min, in which both solvents contain 0.1% formic acid) to give the title compound as a yellow solid. LCMS (ES) [M+1]+ m/z 400.3.

Example 51

Synthesis of 2-methoxy-3-[(1-methylpyrrolidin-3-yl)methoxy]-N-(propan-2-yl)-7,8,9,10-tetrahydrophenanthridin-6-amine formate

The title compound was prepared from 6-chloro-2-methoxy-3-[(1-methylpyrrolidin-3-yl)methoxy]-7,8,9,10-tetrahydrophenanthridine (Intermediate II-6) and propan -2-amine, following a procedure similar to that described above in Example 3. The crude product was purified by reverse preparative HPLC (Prep-C18 column, SunFire 5 pM, 19*150 mm, Waters; MeCN 17 gradient elution). -34 % in water over a period of 7 min, where both solvents contain 0.1% FA) to give the title compound as a dark green solid. LCMS (ES) [M+1]+ m/z 384.3.

Example 52

Synthesis of 9-methoxy-N-(propan-2-yl)-8-[3-(pyrrolidin-1-yl)propoxy]benzo[h]1,6-naphthyridin-5-amine formate

The title compound was prepared from 1-[3-({5-chloro-9-methoxybenzo[h]1,6-naphthyridin-8-yl}oxy)propyl]pyrrolidine (Intermediate 111-3) and propan -2-amine, following a procedure similar to that described above in Example 3. The crude product was purified by reverse preparative HPLC (Prep-C18 column, XBridge 5 pM, 19*150 mm, Waters; MeCN 8 gradient elution). -24% in water over a period of 7 min, where both solvents contain 0.1% FA) to give the title compound as a brown solid. LCMS (ES) [M+1]+ m/z 395.3.

Example 53

Synthesis of 8-methoxy-N,2,2-trimethyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine formate

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl] pyrrolidine (Intermediate 11-4) and ethylamine (2.0 M in THF), following a procedure similar to that described above in Example 3. The crude product was purified by reverse preparative HPLC (Prep-C18 column, OBD 5 pM, 19* 250mm, Waters; gradient elution of 0-40% MeCN in water over a period of 20 min, where both solvents contain 0.1% formic acid, flow rate: 20 mL/min) to give the compound of the title as a brown solid. LCMS (ES) [M+1]+m/z 384.3.

Example 54

Synthesis of 8-methoxy-2,2-dimethyl-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin formate -4-amine

The title compound was prepared from 1-[3-({4-doro-8-methoxy-2,2-dimethylMH,2H,3H-ddopenta[c]quinoNn-7-N}oxy)propyl]pyrrolidine ( Intermediate II-4) and propan-2-amine, following a procedure similar to that described above in Example 3. The crude product was purified by reverse preparative HPLC ((Prep-C18 column, OBD 5 ^M, 19 x 250 mm , Waters; gradient elution from 0-40% MeCN in water over a period of 20 min, where both solvents contain 0.1% formic acid, flow rate: 20 mL/min) to give the title compound as a solid brown LCMS (ES) [M+1]+ m/z 412.3.

Example 55

Synthesis of N-cyclopropyl-9-methoxy-8-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,4H-pyrano[3,4-c]-quinolin-5-amine formate

The title compound was prepared from 1-[3-({5-chloro-9-methoxy-1H,2H,4H-pyrano[3,4-c]quinolin-8-yl}oxy)propyl]pyrrolidine ( Intermediate 111-6) and cyclopropanamine, following a procedure similar to that described above in Example 3, except that the reaction was carried out in a microwave reactor at 80 °C for 3 h. The crude product was purified by reverse preparative HPLC (Prep-C 18 column, XBridge 5 ^M, 19 x 150 mm, Waters; gradient elution of 13-35% MeCN in water over a period of 7 min, in which both solvents contain 0.1% formic acid) to give the title compound as a yellow solid. LCMS (ES) [M+1]+ m/z 398.2.

Example 56

Synthesis of 9-methoxy-8-[3-(pyrrolidin-1-yl)propoxy]pyrazolo[1,5-c]quinazolin-5-ol formate

Stage 1

A mixture of 1H-pyrazol-5-ylboronic acid (186.90 mg; 1.67 mmol; 1.20 eq.), potassium carbonate (384.17 mg; 2.78 mmol; 2.00 eq.) and 1-[3-(4-bromo-2- methoxy-5-nitrophenoxy)-propyl]pyrrolidine (500.00 mg; 1.39 mmol; 1.00 eq.) in a mixed solvent of dimethylethane (2.0 mL) and water (0.6 mL) in a sealed vial was purged with N2 for 10 min. . Pd(PPh3)4 (80 mg, 0.07 mmol, 0.05 eq.) and Cul (27 mg, 0.14 mmol, 0.10 eq.) were added to the mixture. The vial was sealed and the mixture was left under stirring at 100 °C for 16 h. The crude reaction mixture was cooled to rt, quenched with water and extracted with 30% iPrOH/chloroform. The organic layers were combined and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with 5-15% solvent A in CH2Q 2 (solvent A is 0.1% NH4OH/10% MeOH/CH2Ch) to give 5-(5-methoxy -2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-1H-pyrazole as a brown syrup (310 mg, 64%). lCm S (ES) [M+1]+ m/z 347.3.

Stage 2

To a solution of 5-{5-methoxy-2-nitro-4-[3-(pyrrolidin-1-yl)propoxy]phenyl}-1H-pyrazole (310.00 mg; 0.89 mol) in MeOH (8 mL) was added added Pd/C (30 mg). The reaction flask was purged once with nitrogen and twice with hydrogen. The mixture was allowed to stir at 60 °C for 2.5 h. The solid was filtered through a small pad of Celite. Removal of the organic solvent under reduced pressure gave 4-methoxy-2-(1H-pyrazol-5-yl)-5-[3-(pyrrolidin-1-yl)propoxy]aniline as a brown oil (252 mg, 92% ). LCMS (ES) [M+1]+ m/z 317.3.

Stage 3

To a flask charged with 4-methoxy-2-(1H-pyrazol-5-yl)-5-[3-(pyrrolidin-1-yl)propoxy]aniline (152.00 mg; 0.48 mmol; 1.00 eq.) was added anhydrous CH2Q 2 (4 mL) followed by N,N-diisopropylethylamine (0.2 mL). The resulting solution was cooled to -78 °C and bis(trichloromethyl) carbonate (49.90 mg; 0.17 mmol; 0.35 eq.) was added to the mixture. After stirring at -78 °C for 20 min, the reaction flask was removed from the bath and allowed to stir at room temperature for 2 h. The reaction mixture was quenched with water and extracted three times with 30% PrOH/chloroform. The organic layers were combined and concentrated under reduced pressure. The residue was dissolved in DMSO and subjected to purification by reverse preparative HPLC (Prep-C18 column, 5 ^M OBD, 19 x 250 mm, Waters; gradient elution from 0-40% MeCN in water over a period of 20 min, in which both solvents contain acid 0.1% formic, flow rate: 20 mL/min) to give the title compound as a white solid (33 mg, 19%).

LCMS (ES) [M+1]+ m/z 343.3.

Example 57

Synthesis of 9-methoxy-N-methyl-8-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,4H-pyrano[3,4-c]quinolin-5-amine formate

The title compound was prepared from 1-[3-({5-chloro-9-methoxy-1H,2H,4H-pyrano[3,4-c]-quinolin-8-yl}oxy)propyl]pyrrolidine (Intermediate compound MI-6) and methylamine (2.0 M in THF), following a procedure similar to that described above in Example 3, except that the reaction was carried out in a microwave reactor at 120 °C for 1.0 h. The crude product was purified by reverse preparative HPLC (Prep-C18 column, XBridge 5 mM, 19 x 150 mm, Waters; gradient elution of 13-35% MeCN in water over a period of 7 min, in which both solvents contain 0.1% formic acid) to give the title compound as a yellow solid. LCMS (ES) [M+1]+ m/z 372.2.

Example 58

Synthesis of N-ethyl-9-methoxy-8-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,4H-pyrano[3,4-c]quinolin-5-amine formate

The title compound was prepared from 1-[3-({5-chloro-9-methoxy-1H,2H,4H-pyrano[3,4-c]quinolin-8-yl}oxy)propyl]pyrrolidine ( Intermediate 111-6) and ethylamine (2.0 M in THF), following a procedure similar to that described above in Example 3, except that the reaction was carried out in a microwave reactor at 120 °C for 1.0 h. The crude product was purified by reverse preparative HPLC (Prep-C18 column, XBridge 5 mM, 19 x 150 mm, Waters; gradient elution of 13-35% MeCN in water over a period of 7 min, in which both solvents contain 0.1% formic acid) to give the title compound as a yellow solid. LCMS (ES) [M+1]+ m/z 386.2.

Example 59

Synthesis of 8-methoxy-N-methyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,3H-furo[3,4-c]quinolin-4-amine formate

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,3H-furo[3,4-c]quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate 111-7) and methylamine (2.0 N in THF), following a procedure similar to that described above in Example 3, except that the reaction was carried out in a microwave reactor at 100 °C for 1.0 h. The crude product was purified by reverse preparative HPLC (Prep-C18 column, XBridge 5 ^M, 19 x 150 mm, Waters; gradient elution of 13-35% MeCN in water over a period of 7 min, in which both solvents contain 0.1% formic acid) to give the title compound as a light brown solid. 1H NMR (300 MHz, CD3OD-d6, ppm): 8.48 (br, 1H), 7.38 (s, 1H), 6.92 (s, 1H), 5.34 (s, 2H), 5.05 (s, 2H), 4.31 - 4.28 (m, 2H), 3.93 (s, 3H), 3.61 - 3.47 (m, 6H), 3.10 (s, 3H), 2.38-2.36 (m, 2H), 2.15-2.10 (m, 4H). LCMS (ES) [M+1]+ m/z 358.2.

Example 60

S ynthesis of N -ethyl-8-m ethoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,3H-furo[3,4-c]quinolin-4 formate -am ina

The title compound was prepared from 1-[3-({4-doro-8-methoxy-1H,3H-iuro[3,4-c]quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate 111-7) and ethylamine (2.0 N in THF), following a procedure similar to that described above in Example 3, except that the reaction was carried out in a microwave reactor at 100 °C for 1.0 h. The crude product was purified by reverse preparative HPLC (Prep-C18 column, XBridge 5 ^M, 19 x 150 mm, Waters; gradient elution of 13-35% MeCN in water over a period of 7 min, in which both solvents contain 0.1% formic acid) to give the title compound as a light brown solid. LCMS (ES) [M+1]+ m/z 372.2.

Example 61

Synthesis of 2-methoxy-6-(methylamino)-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-8-ol formate

Stage 1

In a 40 ml sealed tube vial, purged and maintained with an inert atmosphere of nitrogen, a mixture of 8-(benzyloxy)-6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl )propoxy]-7,8,9,10-tetrahydrophenanthridine (Intermediate 111-8) (1.00 g, 2.08 mmol, 1.00 eq.), anhydrous 1,4-dioxane (10 mL), MeNH2 (5.2 mL, 2 N in Th F, 10.4 mmol, 5.00 eq.), third-generation BrettPhos precatalyst (189 mg, 0.208 mmol, 0.10 eq.), t-BuONa (400 mg, 4.16 mmol, 2.00 eq.), and subsequently MS of 4Á (400mg). The vial was sealed and the resulting solution was allowed to stir for 16 h at 90 °C under a nitrogen atmosphere. The mixture was cooled to rt, diluted with 100 mL of 10% MeOH/CH2Cl2, and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give a crude product of 8-(benzyloxy)-2-methoxy-N-methyl-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10- tetrahydrophenanthridin-6-amine as crude brown oil (956 mg). LCMS (ES) [M+1]+ m/z 476.4.

Stage 2

In a solution at 0 °C of 8-(benzyloxy)-2-methoxy-N-methyl-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-6-amine (500 mg, 1.05 mmol, 1.00 eq.) in CH2Cl2 (8 mL) TMSI (421 mg, 2.10 mmol, 2.00 eq.) was added dropwise with stirring. The resulting mixture was allowed to stir at room temperature for 4 h. The reaction mixture was then quenched with saturated aqueous NaHCO3. The mixture was diluted with 10% MeOH/CH2Cl2, dried over anhydrous sodium sulfate, and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was diluted with 5 mL N,N-dimethylformamide, filtered and subjected to preparative reverse-phase HPLC (Prep-C18 column, SunFire 5 ^M, 19 x 150 mm, Waters; MeCN 18 gradient elution). %-22% in water over a period of 8 min, where both solvents contain 0.05% FA) to give the title compound as a green solid. LCMS (ES) [M+1]+ m/z 386.2.

Example 62

Synthesis of 1-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)cyclopropane-1-acid formate carboxylic

A mixture of 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]-pyrrolidine (Intermediate II-1) (150 mg , 0.42 mmol, 1.00 eq.), 1,4-dioxane (5 mL), and t-BuONa (160 mg, 1.66 mmol, 4.00 eq.) in a microwave reaction vial was purged with N2 for 5 min. 1-Aminocyclopropane-1-carbonitrile hydrochloride (103 mg, 0.86 mol, 2.1 eq.) and third-generation BrettPhos precatalyst (32 mg, 0.04 mmol, 0.05 eq.) were added to the solution. After purging with N2 for an additional 2 min, the resulting solution was sealed and subjected to a microwave reactor (130 °C, 2.5 h). The reaction mixture was allowed to cool to rt and quenched with H2O. The resulting mixture was allowed to stir at rt for 2h. After removal of volatiles under reduced pressure, the residue was re-dissolved in DMSO, filtered and subjected to reverse preparative HPLC (Prep-C18 column, 5 ^M OBD, 19*250 mm, Waters; gradient elution). 0-40% MeCN in water over a period of 20 min, both solvents containing 0.1% formic acid, flow rate: 20 mL/min) to give the title compound as a brown oil (65 mg, 38% ). LCMS (ES) [M+1]+ m/z 426.2.

Example 63

Synthesis of 6-fluoro-8-methoxy-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4 formate -amine

The title compound was prepared from 1-[3-({4-chloro-6-fluoro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine ( Intermediate 11-7) and propan-2-amine, following a procedure similar to that described above in Example 3. The crude product was purified by reverse preparative HPLC (Prep-C18 column, XBridge 5 mM, 19*150 mm, Waters gradient elution of 13-35% MeCN in water over a period of 7 min, where both solvents contain 0.1% formic acid) to give the title compound as a light brown oil. LCMS (ES) [M+1]+ m/z 402.2.

Example 64

Synthesis of 3-({2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-6-yl}amino)cyclobutan-1-ol formate

The title compound was prepared from 6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine (Intermediate II-2) and trans -3-aminocyclobutan-1-ol, following a procedure similar to that described above in Example 3. The crude product was purified by reverse preparative HPLC (Prep-C18 column, XBridge 5 ^M, 19*150 mm, Waters; elution on gradient of 10-28% MeCN in water over a period of 7 min, with both solvents containing 0.1% formic acid (FA)) to give the title compound as a yellow solid. LCMS (ES) [M+1]+ m/z 426.3.

Example 65

Synthesis of 8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-N-(2,2,2-trifluoroethyl)-1H,2H,3H-cyclopenta[c]quinolin-4-amine formate

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate II -1) and 2,2,2-trifluoroethane-1-amine, following a procedure similar to that described above in Example 3. The crude mixture was filtered and subjected to preparative reverse-phase HPLC purification (Prep-C18 column, XBridge 5 ^M, 19*150 mm, Waters, gradient elution of 10-25% MeCN in water over a period of 7 min, where both solvents contain 0.1% formic acid (FA) to give compound of the title as an off-white solid. LCMS (ES) [M+1]+ m/z 424.3.

Example 66

Synthesis of 8-m ethoxy-7-[3-(pyrrolidin-1-yl)propoxy]-N -(3,3,3-trifluoropropyl)-1H,2H,3H-cyclopenta[c]quinine lin-4-am ina

The title compound was prepared from 1-[3-({4-doro-8-methoxy-1H,2H,3H-cidopenta-[c]quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate II -1) and 3,3,3-trifluoropropan-1-amine, following a procedure similar to that described above in Example 3, except that the crude mixture was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with 10% MeOH/CH2Cl2 to give the title compound as a yellow solid. LCMS (ES) [M+1]+ m/z: 438.2.

Example 67

Synthesis of 2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-N-(2,2,2-trifluoroethyl)-7,8,9,10-tetrahydrophenanthridin-6-amine formate

The title compound was prepared from 6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine (Intermediate II-2) and 2 ,2,2-trifluoroethane-1-amine, following a procedure similar to that described above in Example 3, except that the crude mixture was filtered and subjected to preparative reverse-phase HPLC purification (Prep-C 18 column, XBridge 5 ^M, 19 x 150 mm, Waters, gradient elution of 12-27% MeCN in water over a period of 7 min, where both solvents contain 0.1% formic acid (FA) to give the title compound as an off-white solid (116.3 mg, 36%). LCMS (ES) [M+1]+ m/z 438.4. Example 68

Synthesis of 2-methoxy-6-[(propan-2-yl)amino]-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-8-ol trifluoroacetate

The title compound was prepared from 8-(benzyloxy)-6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine (Intermediate 111-8) following a procedure similar to that described above in Example 61, except that propan-2-amine was used instead of MeNH2. The final step crude product purified by reverse preparative HPLC (Prep-C18 column, SunFire 5 ^M, 19 x 150 mm, Waters; gradient elution of 8-22% MeCN in water over a period of 8 min, in in which both solvents contain 0.1% trifluoroacetic acid (TFA)) to give the title compound as a light brown oil (90.0 mg, 18% over 2 steps). LCMS (ES) [M+1]+ m/z 414.2.

Example 69

Synthesis of 8-Methoxy-N-methyl-N-phenyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine trifluoroacetate

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta-[c]quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate II -1) and N-methylaniline following a procedure similar to that described above in Example 5, except that the reaction solution was allowed to stir at 100 °C under N2 atmosphere for 16 h.

The crude mixture was filtered and subjected to preparative reverse-phase HPLC purification (Prep-C18 column, SunFire 5 ^M, 19 x 150 mm, Waters; gradient elution of 5-20% MeCN in water over a period of 1 min and 20-35% MeCN in water over a period of 9 min, where both solvents contain 0.1% trifluoroacetic acid (TFA)) to give the title compound as a yellow solid. LCMS (ES) [M+1]+ m/z 432.2.

Example 70

Synthesis of 1-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}pyrrolidine formate

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate II- 1) and pyrrolidine, following a procedure similar to that described above in Example 5, except that the reaction solution was allowed to stir at 100 °C under N2 for 16 h. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC purification (Prep-C18 column, XBridge 5 ^M, 19 x 150 mm, Waters; gradient elution from 5-22% MeCN in water over a 7 min period, where both solvents contain 0.1% formic acid (FA) to give the title compound as a dark green solid. LCMS (ES) [M+1]+ m/z 396.2.

Example 71

Synthesis of 9-methoxy-3-methyl-N-(propan-2-yl)-8-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H,4H-benzo[c]2 formate ,7-naphthyridine-5-amine

In a sealed 8 ml vial, a mixture of 1-[3-({5-chloro-9-methoxy-3-methyl-1H,2H,3H,4H-benzo[c]2,7-naphthyridine - 8-yl}oxy)propyl]pyrrolidine (Intermediate III-9) (110 mg, 0.281 mmol, 1.00 eq.), dry 1,4-dioxane (3 mL), propan-2-amine (83 mg, 1.40 mmol , 5.00 eq.), t-BuONa (81 mg, 0.843 mmol, 3.00 eq.) and later third-generation BrettPhos precatalyst (12 mg, 0.013 mmol, 0.05 eq.). The resulting mixture was allowed to stir at 100 °C under N2 atmosphere for 1 hour. The mixture was concentrated under reduced pressure and the resulting residue was dissolved in N,N-dimethylformamide (5 mL) and subjected to reverse preparative HPLC (Prep-C18 column, XBridge 5 mM, 19 x 150 mm, Waters; gradient elution of 13-35% MeCN in water over a period of 7 min, where both solvents contain 0.1% formic acid) to give the title compound as a brown solid (72 mg, 62%). LCMS (ES) [M+1]+ m/z 413.3.

Example 72

Synthesis of 8-Methoxy-N-methyl-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4 trifluoroacetate -amine

8-Methoxy-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin- 4-amine (Example 3) (110 mg, 0.29 mmol, 1.00 eq.), ethanol (10 mL), CH2O (37% aqueous) (0.23 mL, 2.90 mmol, 10.00 eq.), then NaBH3CN (54 mg, 0.86 mmol, 3.00 eq.). The resulting solution was allowed to stir at 120 °C for 16 h. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC purification (Prep-C18 column, SunFire 5 ^M, 19 x 150 mm, Waters; gradient elution of 20-32% MeCN in water over a period of 9.5 min, where both solvents contain 0.1% trifluoroacetic acid (TFA)) to give the title compound as a yellow solid. LCMS (ES) [M+1]+ m/z 398.3.

Example 73

Synthesis of N -cidopentyl-8-m ethoxy-N -m ethyl-7 -[3 -(pyrolid in -1-yl)propoxy]-1H,2H,3H -cidopenta[c]qu inolin- trifluoroacetate 4-am ina

The title compound was prepared from N-cyclopentyl-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine (Example 8 ) following a procedure similar to that described above in Example 72, except that the reaction solution was allowed to stir at 120 °C for 2 days. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC purification (Prep-C18 column, SunFire 5 ^M, 19*150 mm, Waters; gradient elution of 20-42% MeCN in water over a period of 9.5 min, where both solvents contain 0.1% trifluoroacetic acid (TFA)) to give the title compound as a yellow semi-solid. LCMS (ES) [M+1 ]+ m/z 424.3.

Example 74

Synthesis of N-ethyl-8-methoxy-2,2-dimethyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine formate

formate

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl] pyrrolidine (Intermediate 11-4) and ethylamine (2.0 M in THF), following a procedure similar to that described above in Example 3. The crude product was purified by reverse preparative HPLC (Prep-C18 column, OBD 5 ^M, 19 * 250mm, Waters; gradient elution of 0-40% MeCN in water over a period of 20 min, where both solvents contain 0.1% formic acid, flow rate: 20 mL/min) to give compound of the title as a brown solid. LCMS (ES) [M+1]+m/z 398.3.

Example 75

Synthesis of 1-[3-({9-methoxy-2,2-dimethyl-1H,2H,3H,4H-benzo[h]1,6-naphthyridin-8-yl}oxy)propyl]pyrrolidine formate

To an 8 ml vial was added dioxane/H2O (4 ml, V/V = 5/1), 1-[3-([5-chloro-9-methoxy-2,2-dimethyl-1H,2H, 3H,4H-benzo[h]1,6-naphthyridin-8-yl]oxy)propyl]pyrrolidine (Intermediate IN-10) (200 mg, 0.50 mmol, 1.00 eq.), K3PO4 (212 mg, 1.00 mmol, 2.00 eq.) and Pd(Amfos)Cl2 (35 mg, 0.05 mmol, 0.10 eq.). The resulting mixture was stirred for 16 h at 90 °C under N2 atmosphere. The mixture was concentrated in vacuo. To the residue was added DMF (5 mL). The mixture was filtered and subjected to preparative reverse-phase HPLC (Prep-C18 column, XBridge 5 ^M, 19*150 mm, Waters; gradient elution from 5% MeCN in water to 15% MeCN in water over a 6 min period, where both solvents contain 0.1% formic acid) to give the title compound (7.9 mg, 4%) as a brown semi-solid. 1H NMR (300 MHz, CD3OD-d4): 58.10 (s, 1H), 7.78 (s, 1H), 7.23 (s, 1H), 4.34 (br, 2H), 4.06 (s, 3H), 3.56 - 3.48 (m, 6H), 2.96 (t, J =6.3 Hz, 2H), 2.38 (br, 2H), 2.15 (br, 4H), 1.91 (t, J = 6.3 Hz, 2H), 1.49 (s, 6H) . LCMS (ES) [M+1]+ m/z 370.2.

Example 76

Synthesis of 1-[3-({5-cyclopropyl-9-methoxy-2,2-dimethyl-1H,2H,3H,4H-benzo[h]1,6-naphthyridin-8-yl}oxy)propyl formate ] pyrrolidine

In a 40 ml vial, a mixture of 1-[3-([5-chloro-9-methoxy-2,2-dimethyl-1H,2H,3H,4H-benzo[h]1,6-naphthyridine -8-yl]oxy)propM]pyrroMdine (Intermediate III-10) (700 mg, 1.73 mmol, 1.00 eq.), toluene (20 mL), water (2 mL), cyclopropylboronic acid (1.09 g, 12.69 mmol, 5.00 eq.), Pd(dppf)Cl2 (115 mg, 0.16 mmol, 0.10 eq.), and potassium carbonate (1.09 g, 7.89 mmol, 5.00 eq.). The resulting mixture was stirred for 2 hours at 90°C under N2 and then concentrated in vacuo. The residue was diluted with DMF (5 mL), filtered and subjected to reverse preparative HPLC (Prep-C18, 20-45 ^M, 120 g, Tianjin Bonna-Agela Technologies; gradient elution of 5% MeCN in water to 30% MeCN in water over a period of 10 min, where both solvents contain 0.1% formic acid) to give the title compound (59.8 mg, 6%) as a brown semi-solid. 1H NMR (300 MHz, DMSO-ds) 58.23 (s, 3H), 7.45 (s, 1H), 7.08 (s, 1H), 6.86 (s, 1H), 4.10 (t, J = 6.3 Hz, 2H) , 3.90 (s, 3H), 2.90 (t, J = 6.3 Hz, 2H), 2.76 - 2.67 (m, 6H), 2.21-2.13 (m, 1H), 2.08 - 1.96 (m, 2H), 1.77 - 1.75 (m, 6H), 1.31 (s, 6H), 1.05 - 0.88 (m, 4H). LCMS (ES) [M+1]+ m/z 410.5.

Example 77

Synthesis of 1-(3-{[9-methoxy-2,2-dimethyl-5-(propan-2-yl)-1H,2H,3H,4H-benzo[h]1,6-naphthyridine-8 formate -yl]oxy}propyl)pyrrolidine

Stage 1

In a 40 ml vial, a mixture of 1-[3-([5-chloro-9-methoxy-2,2-dimethyl-1H,2H,3H,4H-benzo[h]1,6-naphthyridine -8-yl]oxy)propyl]pyrrolidine (Intermediate III-10) (700 mg, 1.74 mmol, 1.00 eq.), ethylene glycol dimethyl ether (20 mL), water (2 mL), 4.4.5, 5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.46 g, 8.70 mmol, 5.00 eq.), Pd(PPh3)4 (402 mg, 0.348 mmol, 0.20 eq.) and Cs2CO3 (2.83 g, 8.70 mmol, 5.00 eq.). The resulting mixture was stirred for 2 hours at 90°C under N2 atmosphere. The reaction mixture was cooled to rt and concentrated in vacuo. The residue was diluted with DMF (5 mL), filtered and subjected to reverse preparative HPLC (Prep-C18, 20-45 ^M, 120 g, Tianjin Bonna-Agela Technologies; gradient elution of 5% MeCN in water to 30% MeCN in water over a period of 10 min, where both solvents contain 0.1% formic acid) to give 9-methoxy-2,2-dimethyl-5-(prop-1-en-2-yl )-8-(3-(pyrrolidin-1-yl)propoxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine (316.0 mg, 45%) as a brown oil. LCMS (ES) [M+1]+ m/z 410.5.

Stage 2

In a 25 ml round bottom flask, a mixture of 1-(3-[[9-methoxy-2,2-dimethyl-5-(prop-1-en-2-yl)-1H, 2H, 3H,4H-benzo[h]1,6-naphthyridin-8-yl]oxy]propyl)pyrrolidine (316 mg, 0.77 mmol, 1.00 eq.), methanol (10 mL), and 10% Pd/C (300 mg ). The mixture was degassed and purged with hydrogen 3 times. The resulting mixture was stirred for 1 h under H2 atmosphere at room temperature. The mixture was filtered and the filtrate was subjected to reverse preparative HPLC (Prep-C18 column, XBridge 5 ^M, 19*150 mm, Waters; gradient elution from 9% MeCN in water to 18% MeCN in water over a 6 min period, where both solvents contain 0.1% formic acid) to give the title compound (17.2 mg, 13%) as a yellow semi-solid. 1H NMR (300 MHz, DMSO-de) 58.27 (s, 3H), 7.54 (s, 1H), 7.33 (s, 1H), 7.31 (s, 1H), 4.14 (t, J = 6.3 Hz, 2H) , 3.92 (s, 3H), 3.40 - 3.31 (m, 1H), 2.82 - 2.67 (m, 8H), 2.08 - 2.01 (m, 2H), 1.76 - 1.74 (m, 6H), 1.33 (s, 6H) , 1.28 (d, J = 6.6 Hz, 6H). LCMS (ES) [M+1]+ m/z 412.5.

Example 78

Synthesis of 1-[3-({9-methoxy-2,2,5-trimethyl-1H,2H,3H,4H-benzo[h]1,6-naphthyridin-8-yl}oxy)propyl]pyrrolidine

In a 40 ml vial, a mixture of 1-[3-([5-chloro-9-methoxy-2,2-dimethyl-1H,2H,3H,4H-benzo[h]1,6-naphthyridine -8-yl]oxy)propM]pyrrolidine (Intermediate III-10) (700 mg, 1.73 mmol, 1.00 eq.), dioxane (20 mL), water (2 mL), methyl boronic acid (1.5 g, 25.06 mmol , 10.00 eq.), Pd(PPh3)4 (402 mg, 0.35 mmol, 0.20 eq.), and potassium carbonate (1.02 g, 7.38 mmol, 5.00 eq.). The resulting mixture was stirred for 2 hours at 90°C under N2 atmosphere. The crude reaction mixture was filtered and subjected to reverse preparative HPLC (Prep-C18, 20-45 mM, 120 g, Tianjin Bonna-Agela Technologies; gradient elution from 5 % MeCN in water to 25 % MeCN in water over a period of 8 min, where both solvents contain 0.1% formic acid) to give the title compound as a brown semi-solid (114.6, 13%). 1H NMR (300 MHz, DMSO-ds) 58.29 (s, 3H), 7.75 (s, 1H), 7.63 (s, 1H), 7.31 (s, 1H), 4.13 (t, J = 6.0 Hz, 2H) , 3.93 (s, 3H), 2.74 - 2.67 (m, 4H), 2.66 - 2.61 (m, 4H), 2.50 (s, 3H), 2.08 - 1.95 (m, 2H), 1.78 - 1.74 (m, 6H) , 1.35 (s, 6H). LCMS (ES) [M+1]+ m/z 384.4

Example 79

Synthesis of 1-[3-({6-cyclopentyl-10-methoxy-1H,2H,3H,4H,5H-azepino[3,2-c]quinolin-9-yl}oxy)propyl]pyrrolidine triflate

The title compound was prepared from 1-[3-({6-chloro-10-methoxy-1H,2H,3H,4H,5H-azepino[3,2-c]quinolin-9-yl}oxy) propyl]pyrrolidine (Intermediate 111-5) and 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, following a procedure similar to that described above in Example 77 above, except that the reaction solution was allowed to stir at 100 °C under N 2 atmosphere for 16 h. The crude was purified by preparative reverse-phase HPLC (Prep-C 18 column, XBridge 5 mM, 19*150 mm, Waters; gradient elution from 17% MeCN in water to 32% MeCN in water over a period of 6 min, where both solvents contain 0.05% TFA) to give the title compound as a viscous brown oil (88.4 mg, 24%). 1H NMR (300 MHz, DMSO-de) 512.23 (br, 1H), 9.69 (br, 1H), 8.48 (br, 1H), 7.65 (s, 1H), 7.53 (s, 1H), 4.21 - 4.17 ( m, 2H), 3.92 (s, 3H), 3.77 - 3.71 (m, 2H), 3.68 - 3.58 (m, 2H), 3.56 - 3.47 (m, 1H), 3.41 - 3.29 (m, 2H), 3.13 - 2.97 (m, 4H), 2.29 -2.21 (m, 2H), 2.10 - 1.70 (m, 16H). LCMS (ES) [M+1]+ m/z 424.3.

example 80

Synthesis of 1-[3-({6-cyclopropyl-10-methoxy-1H,2H,3H,4H,5H-azepino[3,2-c]quinolin-9-yl}oxy)propyl]pyrrolidine trifluoroacetate

In a 40 ml vial, a mixture of 1-[3-({6-chloro-10-methoxy-1H,2H,3H,4H,5H-azepino[3,2-c]quinolin-9-yl }oxy)propyl]pyrrolidine (Intermediate 111-5) (500 mg, 1.28 mmol, 1.00 eq.), toluene (10 mL), cyclopropylboronic acid (222 mg, 2.58 mmol, 2.00 eq.), potassium carbonate (534 mg, 3.86 mmol, 3.00 eq.) and Pd(dppf)Cl2 (98.2 mg, 0.13 mmol, 0.10 eq.). The resulting mixture was stirred for 16 h at 100 °C under N2 atmosphere and then concentrated in vacuo. The residue was dissolved in DMF (5 mL), filtered and subjected to preparative reverse-phase HPLC (Prep-C18 column, XBridge 5 mM, 19*150 mm, Waters; gradient elution from 2% MeCN in water to 25% MeCN in water over a period of 6 min, with both solvents containing 0.05% TFA) to give the title compound as a yellow oil (111.1 mg, 14%). 1H NMR (300 MHz, DMSO-ds) 5 12.33 (s, 1H), 9.67 (br, 1H), 8.44 (br, 1H), 7.64 (s, 1H), 7.43 (s, 1H), 4.18 - 4.15 (m, 2H), 3.92 (s, 3H), 3.77 - 3.71 (m, 2H), 3.69 - 3.61 (m, 2H), 3.36 - 3.28 (m, 2H), 3.22-3.17 (m, 2H), 3.13 -2.99 (m, 2H), 2.31 -2.23 (m, 3H), 2.13- 1.98 (m, 6H), 1.89- 1.80 (m, 2H), 1.18-1.13 (m, 2H), 1.06- 1.00 (m, 2H). LCMS (ES) [M+1]+ m/z 396.3.

Example 81

Synthesis of 1-(3-{[10-methoxy-6-(propan-2-yl)-1H,2H,3H,4H,5H-azepino[3,2-c]quinolin-9-yl]oxy}propyl )pyrrolidine trifluoroacetate

The title compound was prepared from 1-[3-({6-doro-10-methoxy-1H,2H,3H,4H,5H-azepino[3,2-c]quinolin-9-yl}oxy) propyl]pyrrolidine (Intermediate MI-5) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane, following a procedure similar to that described above in Example 79 above, except that the reaction solvents were DME/H2O (V/V = 5/1) and left under stirring at 100 °C under N2 atmosphere for 16 h. The crude product was purified by preparative reverse-phase HPLC (Prep-C18 column, XBridge 5 mM, 19*150 mm, Waters; gradient elution from 16 % MeCN in water to 30 % MeCN in water over a period of 6 min, where both solvents contain 0.05% TFA) to give the title compound as a yellow solid (101.4 mg, 40%). 1H NMR (300 MHz, DMSO-ds) 5 12.35 (br, 1H), 9.86 (br, 1H), 8.53 (br, 1H), 7.66 (s, 1H), 7.55 (s, 1H), 4.21-4.18 (m, 2H), 3.92 (s, 3H), 3.77 - 3.71 (m, 2H), 3.68 - 3.59 (m, 2H), 3.53 - 3.45 (m, 1H), 3.37 - 3.30 (m, 2H), 3.12 - 2.97 (m, 4H), 2.29 - 2.21 (m, 2H), 2.04 - 1.82 (m, 8H), 1.36 (d, J = 6.9 Hz, 6H). LCMS (ES) [M+1]+ m/z 398.2.

Example 82

Synthesis of 1-[3-({10-methoxy-6-methyl-1H,2H,3H,4H,5H-azepino[3,2-c]quinolin-9-yl}oxy)propyl]pyrrolidine trifluoroacetate

In a 40 ml vial, a mixture of 1-[3-({6-chloro-10-methoxy-1H,2H,3H,4H,5H-azepino[3,2-c]quinolin-9-yl } oxy)propyl]pyrrolidine (Intermediate 111-5) (500 mg, 1.28 mmol, 1.00 eq.), dioxane (5 mL), methyl boronic acid (93 mg, 1.55 mmol, 1.20 eq.), Pd(PPh3) 4 (68 mg, 0.064 mmol, 0.05 eq.) and potassium carbonate (534 mg, 3.86 mmol, 3.00 eq.). The mixture was stirred for 16 h at 100 °C under N2 atmosphere and then concentrated in vacuo. The residue was diluted with DMF (10 mL), filtered and subjected to preparative reverse-phase HPLC (Prep-C18 column, 5 mM X Bridge, 19*150 mm, Waters; gradient elution of 17% MeCN in water to 32% MeCN in water over a period of 6 min, where both solvents contain 0.05% trifluoroacetic acid) to give the title compound as a yellow oil (114.3 mg, 18%). 1H NMR (300 MHz, DMSO-de) 59.76 (br, 1H), 8.42 (br, 1H), 7.66 (s, 1H), 7.23 (s, 1H), 4.19 (t, J = 5.7 Hz, 2H) , 3.92 (s, 3H), 3.75 - 3.70 (m, 2H), 3.68 - 3.63 (m, 2H), 3.36 - 3.29 (m, 2H), 3.10 - 3.00 (m, 2H), 2.97 - 2.94 (m, 2H), 2.55 (s, 3H), 2.27 - 2.20 (m, 2H), 2.12 - 1.92 (m, 6H), 1.91 - 1.88 (m, 2H). LCMS (ES) [M+1]+ m/z 370.2.

Example 83

Synthesis of 1-(3-{[4-(cyclopent-1-en-1-yl)-8-methoxy-2,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7 -yl]oxylpropyl)pyrrolidine

In a sealed 8 ml tube under N2 atmosphere, a mixture of 1-[3-([4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c ]quinolin-7-yl]oxy)propyl]pyrrolidine (Intermediate 111-2) (250.00 mg; 0.64 mmol; 1.00 eq.), 1-cyclopenten-1-yl-boronic acid (143.54 mg; 1.28 mmol; 2.00 eq. .), 4-[di(tert-butyl)phosphino]-N,N-dimethylaniline compound with dichloropalladium (2 :1) (90.80 mg; 0.13 mmol; 0.20 eq.) and K3PO4 (680.48 mg; 3.21 mmol; 5.00 eq. .) in toluene (7.50 ml) and water (0.75 ml). The vial was sealed and heated at 60°C for 90 min. Volatiles were removed under reduced pressure and the residue re-dissolved in DMSO, filtered and subjected to preparative reverse-phase HPLC purification (Prep-C18 XSelect column, 5 mM, 19*150 mm, Waters; gradient elution of 0-50% MeCN in water for a period of 20 min, in which both solvents contain 0.1% hydrochloric acid) to give the title compound (110 mg, 32%). LCMS (ES) [M+1]+ m/z 422.1.

Example 84

Synthesis of 4-[(propan-2-yl)amino]-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cidopenta[c]quinolin-8-ol trifluoroacetate

In a 100 ml round bottom flask, a solution of 8-methoxy-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H- cyclopenta[c]quinolin-4-amine (1.0 g, 2.61 mmol, 1.00 eq.), AcOH (20 mL), and 48% HBr aqueous solution (20 mL). The resulting solution was stirred for 16h at 100°C and then concentrated in vacuo. The residue was diluted with DMF (20 mL), filtered and subjected to reverse phase preparative MPLC (Prep-C18, 20-45 mM, 120 g, Tianjin Bonna-Agela Technologies; 10% MeCN gradient elution in water to 25% MeCN in water over a period of 10 min, where both solvents contain 0.05% TFA) to give the title compound as a brown solid (750 mg, 48%). 1H NMR (300 MHz, DMSO-ds) 512.38 (s, 1H), 9.90 (br, 2H), 8.12 (d, J = 8.4 Hz, 1H), 7.59 (s, 1H), 7.11 (s, 1H) , 4.37-4.28 (m, 1H), 4.18 (t, J =5.4 Hz, 2H), 3.71 -3.57 (m, 2H), 3.47-3.33 (m, 2H), 3.21 - 3.00 (m, 4H), 2.92 - 2.86 (m, 2H), 2.23 - 2.10 (m, 4H), 2.07 - 2.00 (m, 2H), 1.99 -1.81 (m, 2H), 1.33 (d, J = 6.3 Hz, 6H). LCMS (ES) [M+1]+ m/z 370.3.

Example 85

Synthesis of 8-methoxy-7-[3-(piperidin-1-yl)propoxy]-N-(propan-2-yl)-1H,2H,3H-cyclopenta[c]quinolin-4-amine formate

The title compound was prepared from 4-chloro-8-methoxy-7-(3-(piperidin-1-yl)propoxy)-2,3-dihydro-1H-cyclopenta[c]quinolone (Intermediate MI- 11) and propan-2-amine, following a procedure similar to that described above in Example 5. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC purification (Prep-C18 column, 5 mM, XBridge, 19 x 150 mm, Waters; gradient elution from 7% MeCN in water to 27% MeCN in water over a period of 6 min, both solvents containing 0.1% formic acid) to give the title compound. title as a yellow solid (197.7 mg, 38%). 1H NMR (300 MHz, DMSO-de) 58.25 (s, 2H), 7.02 (s, 1H), 6.93 (s, 1H), 5.74 (d, J = 7.5 Hz, 1H), 4.44 - 4.34 (m, 1H), 4.09 (t, J = 6.0 Hz, 2H), 3.82 (s, 3H), 3.05 (t, J = 7.2 Hz, 2H), 2.83 - 2.75 (m, 8H), 2.20 - 2.02 (m, 4H ), 1.65 - 1.60 (m, 4H), 1.52 - 1.47 (m, 2H), 1.21 (d, J = 6.9 Hz, 6H). LCMS (ES) [M+1]+ m/z 398.3.

Example 86

Synthesis of 7-[3-(3,3-dimethylpyrrolidin-1-yl)propoxy]-8-methoxy-N-(propan-2-yl)-1H,2H,3H-cyclopenta[c]quinolin-4 formate -amine

The title compound was prepared from 1-[3-([4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl]oxy)propyl]-3,3-dimethylpyrrolidine (Intermediate 111-12) and propan-2-amine, following a procedure similar to that described above in Example 5. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC purification (Prep-C18 column, 5 mM XBridge, 19*150 mm, Waters, gradient elution from 5% MeCN in water to 21% MeCN in water over a period of 6 min, both solvents containing 0.1% formic acid) to give the title compound as a yellow solid (103.1 mg, 20%). 1H NMR (300 MHz, DMSO-ds) 58.21 (s, 2H), 7.01 (s, 1H), 6.93 (s, 1H), 5.72 (d, J =8.1 Hz, 1H), 4.47 - 4.30 (m, 1H), 4.10 (t, J = 6.3 Hz, 2H), 3.82 (s, 3H), 3.05 (t, J =7.2 Hz, 2H), 2.87 - 2.81 (m, 2H), 2.79 - 2.74 (m, 4H ), 2.55 - 2.51 (m ,2H), 2.19 - 2.05 (m, 2H), 2.00 - 1.95 (m, 2H), 1.61 (t, J = 7.2 Hz, 2H), 1.21 (d, J = 6.3 Hz, 6H), 1.08 (s, 6H). LCMS (ES) m/z 412.3 [M+1]+.

Example 87

Synthesis of 8-m ethoxy-2,2-dim ethyl-N -(3-m ethylbutyl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H- formate cidopenta[c] qu inolin-4-am ina

The title compound was prepared from 1-[3-({4-doro-8-methoxy-2,2-dimethyl-1H,2H,3H-cidopenta[c]quinolin-7-yl}oxy)propyl] pyrrolidine (Intermediate II-4) and 3-methylbutanamine, following a procedure similar to that described in Example 3 above. The reaction mixture was filtered and concentrated and the crude was dissolved in dimethylsulfoxide and subjected to preparative reverse-phase HPLC purification (Prep-C18 XSelect column, 5 mM, 19*150 mm, Waters; MeCN gradient elution at 19-35% in water over a period of 7 min, both solvents containing 0.1% formic acid) to give the title compound as a white powder (19 mg, 30%). LCMS (ES) [M+1]+ m/z 440.1.

Example 88

Synthesis of N-[(1S)-1-cyclopropylethyl]-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine formate

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine (Intermediate II -1) and (S)-1-cyclopropylethane-1-amine, following a procedure similar to that described above in Example 5. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC purification (Prep- C18, SunFire 5 mM, 19*150 mm, Waters; gradient elution from 10% MeCN in water to 20% MeCN in water over a period of 10 min, both solvents containing 0.1% FA) to give the title compound as an off-white solid (36.2 mg, 14%). 1H NMR (300 MHz, DMSO) 5 8.14 (s, 0.4H), 7.00 (s, 1H), 6.95 (s, 1H), 5.91 (br, 1H), 4.14 (t, J =6.0 Hz, 2H), 3.83 (s, 3H), 3.81 - 3.76 (m, 1H), 3.33 - 3.23 (m, 6H), 3.09 - 3.04 (m, 2H), 2.85 - 2.73 (m, 2H), 2.18 - 2.13 (m, 4H ), 1.95 - 1.90 (m, 4H), 1.26 (d, J = 6.6 Hz, 3H), 1.09 - 1.01 (m, 1H), 0.49 - 0.33 (m, 3H), 0.23 - 0.18 (m, 1H). LCMS (ES) [M 1]+ m/z 410.2.

Example 89

Synthesis of N-[(1R)-1-cyclopropylethyl]-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine formate

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine (Intermediate II -1) and (R)-1-cyclopropylethane-1-amine, following a procedure similar to that described above in Example 5. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC purification (Prep- C18, SunFire 5 mM, 19x150 mm, Waters; gradient elution from 10% MeCN in water to 20% MeCN in water over a period of 10 min, both solvents containing 0.1% FA) to give compound of the title as an off-white solid (43.2 mg, 17%). 1H NMR (300 MHz, CD3OD) 5 7.45 (s, 1H), 7.19 (s, 1H), 4.31 (t, J =5.4 Hz, 2H), 3.98 (s, 3H), 3.64 - 3.55 (m, 2H ), 3.49 (t, J = 7.2 Hz, 2H), 3.40 -3.28 (m, 5H), 3.02 - 2.97 (m, 2H), 2.39 - 2.32 (m, 4H), 2.15 - 2.10 (m, 4H), 1.45 (d, J = 6.3 Hz, 3H), 1.24 -1.18 (m, 1H), 0.69 - 0.56 (m, 2H), 0.40 - 0.33 (m, 2H). LCMS (ES) [M+1] m/z 410.2.

Example 90

Synthesis of 1-(3-{[8-m ethoxy-4-(5-m ethylfuran-3-yl)-1H,2H,3H-cidopenta[c]quinolin-7-yl]oxy} formate prop il)p irro lid ina

Stage 1

In a 250 mL round bottom flask, a mixture of methyl 4-bromofuran-2-carboxylate (3.0 g, 14.63 mmol, 1.00 eq.), 1,4-dioxane (100 mL), 4.4, 5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (11.1 g, 43.89 mmol, 3.00 eq.), KOAc (4.3 g, 43.89 mmol , 3.00 eq.) and Pd(dppf)Cl2 (534 mg, 0.73 mmol, 0.05 eq.). The resulting mixture was stirred for 16 h at 90 °C under N2 atmosphere. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by silica gel column eluted with ethyl acetate/petroleum ether (1/3) to give 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)furan-2-carboxylate. methyl (1.3 g, 35%) as a yellow solid. LCMS (ES) m/z 253.2 [M+1]+.

Stage 2

In a 100 mL round bottom flask, a mixture of methyl 4-(tetramethyl-1,3,2-dioxaborlan-2-yl)furan-2-carboxylate (500 mg, 1.98 mmol, 1.00 eq.) was placed. , 1,4-dioxane (60 mL), water (10 mL), 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy) -propyl]pyrrolidine (Intermediate II-1) (568.8 mg, 1.58 mmol, 0.80 eq.), Cs2CO3 (1.9 g, 5.94 mmol, 3.00 eq.) and Pd(PPh3)4 (116 mg, 0.10 mmol, 0.05 eq. .). The resulting mixture was stirred for 3 h at 100 °C under N2 atmosphere. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by silica gel column eluted with dichloromethane/methanol (5/1) to give 4-[8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H Methyl -cyclopenta[c]quinolin-4-yl]furan-2-carboxylate (335 mg, 37%) as a gray solid. LCMS (ES) m/z 451.2 [M+1]+.

Stage 3

In a stirred solution of 4-[8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl]furan-2-carboxylate of methyl (330 mg, 0.73 mmol, 1.00 eq.) in THF (20 mL) at 0 °C was added L iAH (56 mg, 1.46 mmol, 2.00 eq.). The resulting mixture was stirred for 1 h and then quenched with water (0.06 mL), followed by the addition of 15% aqueous sodium hydroxide solution (0.06 mL) and water (0.18 mL) successively. The mixture was stirred for 30 minutes and then filtered through a pad of Celite. The filter cake was washed with THF (2 x 10 mL). The combined filtrate was concentrated in vacuo to give 4-[8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl]furan-2 -yl)methanol (220 mg, 71%) as a yellow solid. LCMS (ES) m/z 423.2 [M+1]+.

Stage 4

In a 50 ml round bottom flask, a mixture of (4-[8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin- 4-yl]furan-2-yl)methanol (220 mg, 0.52 mmol, 1.00 eq.), methanol (20 mL), hydrochloride concentrate solution (1.8 mL), and 10% Pd/C (30 mg). The resulting mixture was degassed and purged with H2 several times, then stirred for 30 min at rt. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC (Prep-C18 column, XBridge 5 mM, 19*150 mm, Waters; gradient elution from 4% MeCN in water to 24% MeCN in water over a period of 6 min, where both solvents contain 0.05% FA) to give the title compound as a yellow solid (29.9 mg, 9%). 1H NMR (300 MHz, DMSO-d6): 58.23 (s, 2H), 8.04 (s, 1H), 7.34 (s, 1H), 7.11 (s, 1H), 6.80 (s, 1H), 4.20 (t , J =6.0 Hz, 2H), 3.93 (s, 3H), 3.26-3.13 (m, 4H), 2.87 - 2.78 (m, 6H), 2.35 (s, 3H), 2.28 - 2.21 (m, 2H), 2.18 - 2.05 (m, 2H), 1.80 - 1.72 (m, 4H). LCMS (ES) m/z 407.2 [M+1]+. Example 91

Synthesis of N-butyl-8-methoxy-2,2-dimethyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine formate

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl] pyrrolidine (Intermediate Compound II-4) and 1-butanamine, following a procedure similar to that described in Example 3 above. The reaction mixture was filtered and concentrated and the crude was dissolved in dimethyl sulfoxide and subjected to preparative reverse-phase HPLC purification (Prep-C18 XSelect column, 5 mM, 19*150 mm, Waters; elution in gradient of 0-50 % MeCN in water over a period of 20 min, with both solvents containing 0.1% formic acid) to give the title compound as a white powder (19 mg, 30%). LCMS (ES) [M+1]+ m/z 426.1.

Example 92

Synthesis of 7-[3-(dimethylamino)propoxy]-8-methoxy-N-(propan-2-yl)-1H,2H,3H-cyclopenta[c]quinolin-4-amine formate

The title compound was prepared from [3-([4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl]oxy)propyl]dimethylamine (Intermediate MI-13) and propan-2-amine, following a procedure similar to that described above in Example 5. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC purification (Prep-C18 column, SunFire 5 ^M, 19* 150 mm, Waters, gradient elution from 2% MeCN in water to 19% MeCN in water over a period of 6 min, both solvents containing 0.1% formic acid) to give the title compound as a yellow solid (98.9mg, 25%). 1H NMR (300 MHz, DMSO-da): 8.23 (s, 1H), 7.01 (s, 1H), 6.93 (s, 1H), 5.72 (d, J = 7.8 Hz, 1H), 4.43 - 4.32 (m , 1H), 4.09 (t, J = 6.3 Hz, 2H), 3.82 (s, 3H), 3.05 (t, J = 7.2 Hz, 2H), 2.79 - 2.70 (m, 4H), 2.42 (s, 6H) , 2.19 - 2.11 (m, 2H), 2.05 - 1.97 (m, 2H), 1.20 (d, J = 6.6 Hz, 6H). LCMS (ES) [M+1] m/z 358.2.

Example 93

Synthesis of 7-[3-(diethylamino)propoxy]-8-methoxy-N-(propan-2-yl)-1H,2H,3H-cyclopenta[c]quinolin-4-amine formate

The title compound was prepared from [3-([4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl]oxy)propyl]diethylamine (Intermediate III-14) and propan-2-amine, following a procedure similar to that described above in Example 5. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC purification (Prep-C18 column, 5 µm XBridge, 19 * 150 mm, Waters; gradient elution from 2% MeCN in water to 18% MeCN in water over a period of 6 min, both solvents containing 0.1% formic acid) to give the title compound as a solid yellow (76.3mg, 21%). 1H NMR (300 MHz, DMSO-d6): 8.21 (s, 1H), 6.99 (s, 1H), 6.92 (s, 1H), 5.70 (d, J =8.1 Hz, 1H), 4.43 - 4.32 (m , 1H), 4.09 (t, J = 6.3 Hz, 2H), 3.82 (s, 3H), 3.07 - 3.02 (m, 2H), 2.79 - 2.58 (m, 8H), 2.18 - 2.09 (m, 2H), 1.94 -1.90 (m, 2H), 1.20 (d, J = 6.6 Hz, 6H), 1.02 (t, J = 6.9 Hz, 6H). LCMS (ES) [M+1]+ m/z 386.3.

Example 94

Synthesis of N-tert-butyl-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine formate

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine (Intermediate II -1) and 2-methylpropan-2-amine, following a procedure similar to that described above in Example 6 above, except that the reaction solution was allowed to stir at 50 °C under N2 atmosphere for 3 h. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC (Prep-C18 column, SunFire 5 ^M, 19*150 mm, Waters; gradient elution from 5% MeCN in water to 40% MeCN in water). water over a period of 7 min, where both solvents contain 0.1% FA) to give the title compound as a gray solid (22.5 mg, 13%). 1H NMR (300 MHz, DMSO-d6) 58.23 (s, 1H), 7.00 (s, 1H), 6.92 (s, 1H), 5.05 (s, 1H), 4.09 (t, J = 6.3 Hz, 2H) , 3.82 (s, 3H), 3.05 (t, J = 7.5 Hz, 2H), 2.77 (t, J = 7.5 Hz, 2H), 2.67 (t, J = 7.2 Hz, 2H), 2.62 - 2.59 (m, 4H), 2.17 - 2.08 (m, 2H), 2.01 - 1.95 (m, 2H), 1.77 - 1.72 (m, 4H), 1.51 ( s, 9H). LCMS (ES) [M+1]+ m/z 398.2.

Example 95

Synthesis of N-isobutyl-8-methoxy-2,2-dimethyl-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-cidopenta[c]quinolin-4-amine formate

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl] pyrrolidine (Intermediate Compound II-4) and 2-methylM-propanamine, following a procedure similar to that described in Example 3 above. The reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved in dimethyl sulfoxide and subjected to preparative reverse-phase HPLC purification (Prep-C18 XSelect column, 5 ^M, 19 x 150 mm, Waters; gradient elution from 0-50 % MeCN in water over a period 20 min, where both solvents contain 0.1% formic acid) to give the title compound as a white powder (29 mg, 40%). LCMS (ES) [M+1] m/z 426.1.

Example 96

Synthesis of N-(cyclobutylmethyl)-8-methoxy-2,2-dimethyl-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-cyclopenta[c]quinolin-4- formate amine

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl] pyrrolidine (Intermediate Compound II-4) and cyclobutyl methanamine, following a procedure similar to that described in Example 3 above. The reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved in dimethyl sulfoxide and subjected to preparative reverse-phase HPLC purification (Prep-C18 XSelect column, 5 ^M, 19 x 150 mm, Waters; gradient elution from 0-50% MeCN in water over a period 20 min, where both solvents contain 0.1% formic acid) to give the title compound as a white powder (15 mg, 20%). LCMS (ES) [M+1]+ m/z 438.1.

Example 97

Synthesis of N-(cyclopropylmethyl)-8-methoxy-2,2-dimethyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine formate

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl] pyrrolidine (Intermediate Compound II-4) and cyclopropyl methanamine, following a procedure similar to that described in Example 3 above. The reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved in dimethyl sulfoxide and subjected to preparative reverse-phase HPLC purification (Prep-C18 XSelect column, 5 ^M, 19 x 150 mm, Waters; gradient elution from 0-50% MeCN in water over a period 20 min, where both solvents contain 0.1% formic acid) to give the title compound as a white powder (24 mg, 33%). LCMS (ES) [M+1]+ m/z 424.1.

Example 98

Synthesis of 1-(3-{[8-methoxy-4-(oxolan-3-yl)-1H,2H,3H-cyclopenta[c]quinolin-7-yl]oxy}propyl)pyrrolidine formate

The title compound was prepared from 1-[3-({4-doro-8-methoxMH,2H,3H-ddopenta[c]quinoNn-7-N}oxy)-propN]pyrrolidine (Intermediate II-1 ) and 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, following a procedure similar to that described above in Example 77 above, except that left the reaction solution stirring at 80 °C under N2 atmosphere overnight. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC (Prep-C18 column, XBridge 5 ^M, 19*150 mm, Waters; gradient elution from 5% MeCN in water to 15% MeCN in water). water over a period of 7 min, where both solvents contain 0.1% formic acid) to give the title compound as a pale yellow solid (64.1 mg, 27%). 1H NMR (300 MHz, DMSO-d6): 58.21 (s, 1H), 7.31 (s, 1H), 7.09 (s, 1H), 4.17 (t, J = 6.3 Hz, 2H), 4.10 (t, J =7.8 Hz, 1H), 3.99 - 3.94 (m, 1H), 3.91 (s, 3H), 3.89 - 3.82 (m, 2H), 3.74 - 3.66 (m, 1H), 3.19 (t, J = 7.5 Hz, 2H), 3.08 - 3.03 (m, 2H), 2.77 - 2.67 (m, 6H), 2.36 - 2.16 (m, 4H), 2.04 - 1.98 (m, 2H), 1.79- 1.76 (m, 4H). LCMS (ES) [M+1]+ m/z 397.2.

Example 99

Synthesis of N-[(2S)-butan-2-yl]-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4 formate -amine

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine (Intermediate II -1) and (S)-butan-2-amine, following a procedure similar to that described above in Example 5. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC purification (Prep-C18 column, XBridge 5 ^M, 19*150 mm, Waters, gradient elution from 10% MeCN in water to 10% MeCN in water over a period of 7 min, both solvents containing 0.1% formic acid) to give the title compound (32.3 mg, 13%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 58.16 (s, 1H), 7.03 (s, 1H), 6.94 (s, 1H), 5.72 (d, J =8.1 Hz, 1H), 4.26-4.19 (m, 1H), 4.14 (t, J = 6.0 Hz, 2H), 3.83 (s, 3H), 3.17-3.14 (m, 6H), 3.06 (t, J = 7.5 Hz, 2H), 2.79 - 2.73 (m, 2H ), 2.00 - 2.10 (m, 4H), 1.91 - 1.88 (m, 4H), 1.68- 1.47 (m, 2H), 1.17(d, J = 6.3 Hz, 3H), 0.90 (t, J = 7.5 Hz, 3H). LCMS (ES) [M+1]+ m/z: 398.4.

Example 100

Synthesis of N-[(2R)-butan-2-yl]-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4 formate -amine

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine (Intermediate II -1) and (R)-butan-2-amine, following a procedure similar to that described above in Example 5. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC purification (Prep-C18 column, XBridge 5 ^M, 19*150 mm, Waters, gradient elution from 10% MeCN in water to 20% MeCN in water over a period of 7 min, both solvents containing 0.1% formic acid) to give the title compound (29.3 mg, 12%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 58.15 (s, 1H), 7.03 (s, 1H), 6.95 (s, 1H), 5.74 (d, J =7.8 Hz, 1H), 4.26-4.19 (m, 1H), 4.15 (t, J = 6.3 Hz, 2H), 3.83 (s, 3H), 3.28 - 3.15 (m, 6H), 3.06 (t, J = 7.5 Hz, 2H), 2.83 - 2.72 (m, 2H ), 2.17 - 2.06 (m, 4H), 1.93- 1.84 (m, 4H), 1.68 - 1.47 (m, 2H), 1.17 (d, J = 6.6 Hz, 3H), 0.90 (t, J = 7.5 Hz, 3H). LCMS (ES) [M+1]+ m/z: 398.4.

Example 101

Synthesis of N-(2,2-dimethylpropyl)-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cidopenta[c]quinolin-4-amine formate

The title compound was prepared from 1-[3-({4-doro-8-methoxy-1H,2H,3H-cidopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine (Intermediate II -1) and 2,2-dimethylpropan-1-amine, following a procedure similar to that described above in Example 5. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC purification (Prep-C18 column, 5 ^MX Bridge, 19 * 150 mm, Waters; gradient elution from 17% MeCN in water to 30% MeCN in water over a period of 6 min, both solvents containing 0.1% formic acid) to give the title compound (82.5 mg, 30%) as a brown oil. 1H NMR (300 MHz, DMSO-d6) 58.20 (s, 2H), 6.98 (s, 1H), 6.92 (s, 1H), 5.74 (t, J =6.0 Hz, 1H), 4.10 (t, J = 6.6 Hz, 2H), 3.82 (s, 3H), 3.36 - 3.34 (m, 2H), 3.09 - 3.03 (m, 2H), 2.84 - 2.80 (m, 2H), 2.79 - 2.68 (m, 6H), 2.20 - 2.13 (m, 2H), 2.08 - 2.02 (m, 2H), 1.83 - 1.75 (m, 4H), 0.94 (s, 9H). LCMS (ES) [M+1]+ m/z 412.3.

Example 102

Synthesis of 8-Methoxy-N-[(2-2H)propan-2-yl]-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin- 4-amine

Stage 1

In a 50 mL 3-necked round bottom flask, a mixture of lithium(deuterium)-5-alumane (287.7 mg, 6.85 mmol, 0.50 eq.) in tetrahydrofuran (30 mL) was placed. To the mixture was added N-(propan-2-ylidene)hydroxylamine (1.0 g, 13.68 mmol, 1.00 eq.) dropwise. The resulting solution was stirred for 4 h at 70 °C. After cooling to 0 °C, the reaction was quenched by the addition of sodium sulfate decahydrate (2.0 g). The product was purified by distillation at 1.0 atmosphere and the fractions at 40-60°C were collected as the desired product. These desired fractions were dissolved in 1,4-dioxane solution (5 ml) which was freshly saturated with HCl gas. The resulting mixture was allowed to stir at room temperature for 15 min, concentrated in vacuo to give (2 deuterium)propan-2-amine hydrochloride as a yellow solid (320 mg, 24%). 1H NMR (300 MHz, DMSO-d6): 58.14 (br, 2H), 1.19 (s, 6H).

Stage 2

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine (Intermediate II -1) and (2-deuterium)propan-2-amine hydrochloride, following a procedure similar to that described above in Example 5. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC purification (Prep column -C18, 5 ^M XBridge, 19*150 mm, Waters; gradient elution from 20% MeCN in water to 31% MeCN in water over 9 min, both solvents containing 0.05% TFA) to give the title compound (44.8 mg, 4%) as a yellow semi-solid. 1H NMR (300 MHz, DMSO-d6): 58.26 (s, 2H), 7.01 (s, 1H), 6.93 (s, 1H), 5.72 (s, 1H), 4.11 (t, J = 6.3 Hz, 2H ), 3.82 (s, 3H), 3.05 (t, J = 7.2 Hz, 2H), 2.92 - 2.86 (m, 6H), 2.79-2.74 (m, 2H), 2.18 - 2.02 (m, 4H), 1.85 - 1.77 (m, 4H), 1.20 (s, 6H). LCMS (ES) [M+1]+ m/z 385.2.

Example 103

Synthesis of 8-Methoxy-N-(2-methylpropyl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine trifluoroacetate

The title compound was prepared from 1-[3-({4-dora-8-methoxMH,2H,3H-ddopenta[c]quinolin-7-N}oxy)-prapN]pyrrolidine (Intermediate II-1 ) and 2-methylpropan-1-amine, following a procedure similar to that described above in Example 5. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC purification (Prep-C18 column, XBridge 5 j M , 19*150 mm, Waters; gradient elution from 10% MeCN in water to 35% MeCN in water over a period of 7.5 min, both solvents containing 0.1% trifluoroacetic acid) to give the title compound (179.7 mg, 52%) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) 5 12.56 (s, 1H), 9.77 (br, 1H), 8.49 (br, 1H), 7.63 (s, 1H), 7.20 (s, 1H), 4.19 (t , J = 5.7 Hz, 2H), 3.91 (s, 3H), 3.65 - 3.60 (m, 2H), 3.39 - 3.30 (m, 4H), 3.27 - 3.22 (m, 2H), 3.10 - 2.98 (m, 2H ), 2.94 - 2.89 (m, 2H), 2.27 - 2.15 (m, 4H), 2.06 - 1.98 (m, 3H), 1.91 -1.85 (m, 2H), 0.97 (d, J = 6.6 Hz, 6H). LCMS (ES) [M+1]+ m/z: 398.2.

Example 104

Synthesis of 8-Methoxy-N-propyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine trifluoroacetate

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine (Intermediate II -1) and propan-1-amine, following a procedure similar to that described above in Example 5. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC purification (Prep-C18 column, XBridge 5 |jM , 19*150 mm, Waters; gradient elution from 10% MeCN in water to 34% MeCN in water over a period of 7.5 min, both solvents containing 0.1% trifluoroacetic acid) to give the title compound (126.7 mg, 37%) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) 5 12.54 (s, 1H), 9.80 (br, 1H), 8.53 (t, J = 5.4 Hz, 1H), 7.63 (s, 1H), 7.20 (s, 1H ), 4.18 (t, J = 5.7 Hz, 2H), 3.91 (s, 3H), 3.65 - 3.59 (m, 2H), 3.56 - 3.47 (m, 2H), 3.37 - 3.30 (m, 2H), 3.26 - 3.21 (m, 2H), 3.10 - 3.02 (m, 2H), 2.92 - 2.87 (m, 2H), 2.24 - 2.17 (m, 4H), 2.08- 1.95 (m, 2H), 1.91 - 1.85 (m, 2H ), 1.73 - 1.67 (m, 2H), 0.98 (t, J = 6.9 Hz, 3H). LCMS (ES) [M+1]+ m/z: 384.2.

Example 105

Synthesis of N-cyclopropyl-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine trifluoroacetate

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine (Intermediate II -1) and cyclopropanamine, following a procedure similar to that described above in Example 5. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC purification (Prep-C18 column, XBridge 5 j M, 19*150 mm, Waters; gradient elution from 10% MeCN in water to 30% MeCN in water over a period of 7 min, both solvents containing 0.1% trifluoroacetic acid) to give the title compound (122.0 mg, 36%) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) 5 12.63 (s, 1H), 9.83 (br, 1H), 8.89 (s, 1H), 7.78 (s, 1H), 7.23 (s, 1H), 4.21 (t , J = 5.7 Hz, 2H), 3.92 (s, 3H), 3.66 - 3.58 (m, 2H), 3.38 - 3.30 (m, 2H), 3.23 - 3.18 (m, 2H), 3.13 - 3.02 (m, 2H ), 2.92 - 2.84 (m, 3H), 2.25 - 2.15 (m, 4H), 2.08 - 1.96 (m, 2H), 1.95 - 1.87 (m, 2H), 1.07 - 1.01 (m, 2H), 0.82 - 0.77 (m, 2H). LCMS (ES) [M+1]+ m/z: 382.2.

Example 106

Synthesis of N-ethyl-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine trifluoroacetate The title compound was prepared from 1-[3-({4-doro-8-methoxy-1H,2H,3H-cidopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine (Intermediate II -1) and ethanamine, following a procedure similar to that described above in Example 5. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC purification (Prep-C18 column, 5 mM XBridge, 19*150 mm , Waters; gradient elution from 10 % MeCN in water to 35% MeCN in water over a period of 7.5 min, both solvents containing 0.1% trifluoroacetic acid) to give the title compound (94.7 mg, 29 %) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) 5 12.41 (s, 1H), 9.69 (br, 1H), 8.54 (br, 1H), 7.61 (s, 1H), 7.21 (s, 1H), 4.18 (t , J = 6.0Hz, 2H), 3.91 (s, 3H), 3.65 3.54 (m, 4H), 3.37 - 3.30 (m, 2H), 3.27 - 3.21 (m, 2H), 3.13 - 3.02 (m, 2H) , 2.92 - 2.86 (m, 2H), 2.26 - 2.17 (m, 4H), 2.08 - 2.05 (m, 2H), 1.92 - 1.85 (m, 2H), 1.29 (t, J = 6.9 Hz, 3H). LCMS (ES) [M+1]+ m/z: 370.2.

Example 107

Synthesis of N-cyclohexyl-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine trifluoroacetate

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine (Intermediate II -1) and cyclohexanamine, following a procedure similar to that described above in Example 6 above, except that the reaction solution was allowed to stir at 100 °C under N 2 atmosphere for 2 h. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC (Prep-C18 column, XBridge 5 mM, 19*150 mm, Waters; gradient elution from 10% MeCN in water to 36% MeCN in water over a period of 9 min, where both solvents contain 0.05% TFA) to give the title compound (358.1 mg, 73%) as a solid. 1H NMR (300 MHz, DMSO-de) 512.69 (s, 1H), 9.86 (br, 1H), 8.08 (d, J = 9.0 Hz, 1H), 7.65 (s, 1H), 7.19 (s, 1H) , 4.19 (t, J = 5.7 Hz, 2H), 4.07-4.05 (m, 1H), 3.91 (s, 3H), 3.65-3.63 (m, 2H), 3.37 - 3.35 (m, 2H), 3.23 - 3.20 (m, 2H), 3.12 - 3.02 (m, 2H), 2.91 (t, J = 7.5 Hz, 2H), 2.27 - 2.20 (m, 4H), 2.05 - 1.87 (m, 6H), 1.82 - 1.78 (m , 2H), 1.71 - 1.68 (m, 1H), 1.51 - 1.39 (m, 4H), 1.20 - 1.11 (m, 1H). LCMS (ES) [M+1]+ m/z 424.4.

Example 108

Synthesis of N-(cyclopropylmethyl)-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine trifluoroacetate

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine (Intermediate II -1) and cyclopropyl methanamine, following a procedure similar to that described above in Example 121. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC (Prep-C18 column, 5 mM XBridge, 19*150 mm, Waters; gradient elution from 10% MeCN in water to 36% MeCN in water over a period of 9 min, both solvents containing 0.05% TFA) to give the title compound (289.4 mg, 59%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 5 12.67 (s, 1H), 10.06 (s, 1H), 8.69 (t, J = 5.4 Hz, 1H), 7.67 (s, 1H), 7.18 (s, 1H ), 4.18 (t, J = 5.7 Hz, 2H), 3.90 (s, 3H), 3.66 - 3.63 (m, 2H), 3.49 - 3.44 (m, 2H), 3.37 - 3.35 (m, 2H), 3.23 ( t, J = 7.5 Hz, 2H), 3.10 - 3.07 (m, 2H), 2.91 (t, J = 6.9 Hz, 2H), 2.24 - 2.21 (m, 4H), 2.05 - 2.00 (m, 2H), 1.95 -1.87 (m, 2H), 1.25 -1.16 (m, 1H), 0.57 - 0.52 (m, 2H), 0.39 - 0.33 (m, 2H). LCMS (ES) [M+1]+ m/z 396.4.

Example 109

Synthesis of 1-[3-({4-cyclopentyl-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine formate The title compound was prepared from 1-[3-({4-doro-8-methoxy-1H,2H,3H-cidopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine (Intermediate II -1) and 2-(ddopent-1-en-1-yl)-4,4,5,5-tetrametiM,3,2-dioxaboralane, following a procedure similar to that described above in Example 77 above, except that the The reaction solution was allowed to stir at 80 °C under N2 atmosphere for 5 h. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC (Prep-C18 column, XBridge 5 mM, 19*150 mm, Waters; gradient elution from 5 % MeCN in water to 25 % MeCN in water over a period of 7.5 min, where both solvents contain 0.1% formic acid) to give the title compound (143.7 mg, 64%) as a pale yellow solid. 1H NMR (300 MHz, DMSO-ds): 58.23 (s, 1H), 7.29 (s, 1H), 7.07 (s, 1H), 4.17 (t, J = 6.3 Hz, 2H), 3.90 (s, 3H ), 3.38 - 3.27 (m, 1H), 3.18 (t, J = 7.5 Hz, 2H), 3.04 (t, J = 7.5 Hz, 2H), 2.82 - 2.73 (m, 6H), 2.23 - 2.15 (m, 2H), 2.08 -1.93 (m, 6H), 1.83 - 1.65 (m, 8H). LCMS (ES) [M+1]+ m/z 395.2.

Example 110

Synthesis of 1-[3-({4-cyclohexyl-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine trifluoroacetate

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine (Intermediate II -1) and 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, following a procedure similar to that described above in Example 77 above, except that the reaction solution was allowed to stir at 100 °C under N2 atmosphere for 2 h. The crude product was purified by preparative reverse-phase HPLC (Prep-C18 column, XBridge 5 mM, 19*150 mm, Waters; gradient elution from 10% MeCN in water to 35% MeCN in water over a period of 9.5 min, where both solvents contain 0.1% TFA) to give the title compound (121.6 mg, 30%) as a white solid. 1H NMR (300 MHz, DMSO-de): 59.97 (br, 1H), 7.87 (s, 1H), 7.41 (s, 1H), 4.28 (t, J = 5.7 Hz, 2H), 4.00 (s, 3H ), 3.67 - 3.62 (m, 2H), 3.48 - 3.43 (m, 2H), 3.38 - 3.31 (m, 2H), 3.25 - 3.20 (m, 2H), 3.13 - 3.04 (m, 3H), 2.33 - 2.24 (m, 4H), 2.10 - 2.04 (m, 2H), 1.92 - 1.75 (m, 9H), 1.46 - 1.31 (m, 3H). LCMS (ES) [M+1]+ m/z 409.3.

Example 111

Synthesis of 1-[3-({8-methoxy-4-phenyl-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine formate

In a 25 mL round bottom flask, 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine ( Intermediate II-1) 1 (200 mg, 0.55 mmol, 1.00 eq.), 1,4-dioxane (5 mL), water (0.5 mL), phenylboronic acid (101 mg, 0.83 mmol, 1.50 eq.), carbonate potassium (153 mg, 1.11 mmol, 2.00 eq.) and Pd(PPh3)4 (64 mg, 0.06 mmol, 0.10 eq.). The mixture was degassed in vacuo and purged several times with N2. The resulting solution was allowed to stir at 110 °C under N2 atmosphere for 2 h. The crude reaction mixture was filtered and subjected to reverse preparative HPLC (Prep-C18, 20-45 mM, 120 g, Tianjin Bonna-Agela Technologies; gradient elution from 15% MeCN in water to 15% MeCN in water over a period of 5 min, 15% MeCN in water to 30% MeCN in water over a further period of 8 min, with both solvents containing 0.1% formic acid) to give the title compound (68.7 mg, 28 %) as a white solid. 1H NMR (300 MHz, DMSO-d6) 58.21 (s, 1H), 7.87 (d, J = 6.9 Hz, 2H), 7.57-7.44 (m, 3H), 7.42 (s, 1H), 7.16 (s, 1H), 4.19 (t, J = 6.6 Hz, 2H), 3.95 (s, 3H), 3.30 - 3.17 (m, 4H), 2.67 (t, J = 6.9 Hz, 2H), 3.63 - 3.55 (m, 4H ), 2.21 (t, J = 7.2 Hz, 2H), 2.02 (t, J = 7.2 Hz, 2H), 1.75 - 1.70 (m, 4H). LCMS (ES) [M+1] m/z: 403.1.

Example 112

Synthesis of 8-Methoxy-7-[3-(morpholin-4-yl)propoxy]-N-(propan-2-yl)-1H,2H,3H-cyclopenta[c]quinolin-4-amine trifluoroacetate

The title compound was prepared from 4-[3-([4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl]oxy)propyl]morpholine (Intermediate III- 15) and propan-2-amine, following a procedure similar to that described above in Example 5. The crude reaction mixture was filtered and subjected to preparative reverse-phase HPLC (Prep-C18 column, 5 ^M, X Bridge, 19 x 150 mm, Waters; gradient elution from 4% MeCN in water to 24% MeCN in water over a period of 6 min, both solvents containing 0.05% TFA) to give the title compound (251.4 mg, 38%) as a brown oil. 1H NMR (300 MHz, DMSO-da) 5 12.41 (br, 1H), 9.91 (br, 1H), 8.18 (d, J = 8.7 Hz, 1H), 7.63 (s, 1H), 7.21(s, 1H ), 4.41 -4.25 (m, 1H), 4.19 (t, J = 5.7 Hz, 2H), 4.12 - 3.96 (m, 2H), 3.91 (s, 3H), 3.72 - 3.60 (m, 2H), 3.60 - 3.46 (m, 2H), 3.30 - 3.28 (m, 2H), 3.26 - 3.21 (m, 2H), 3.20 - 3.01 (m, 2H), 2.93 - 2.88 (m, 2H), 2.31 - 2.14 (m, 4H ), 1.34 (d, J = 6.9 Hz, 6H). LCMS (ES) [M+1]+ m/z 400.2.

Example 113

Synthesis of 1-[3-({4-cyclopentyl-8-methoxy-2,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl}oxy)propyl]pyrrolidine hydrochloride

A solution of 1-(3-{[4-(cyclopent-1-en-1-yl)-8-methoxy-2,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c]quinolin- 7-yl]oxy}propyl)pyrrolidine (Example 83, 110.00 mg; 0.26 mmol; 1.00 eq.) in methanol (5.50 mL) was purged with nitrogen. Palladium on carbon (2.78 mg; 0.03 mmol; 0.10 eq.) was added to the solution and the flask was purged with nitrogen once more. The flask was filled with hydrogen and the reaction mixture was allowed to stir under hydrogen atmosphere at room temperature overnight. The crude reaction mixture was filtered over Celite and subjected to preparative reverse-phase HPLC purification (Prep-C18 XSelect column, 5 ^M, 19 x 150 mm, Waters; gradient elution from 0-50% MeCN in water over a period of 20 min, where both solvents contain 0.1% hydrochloric acid) to give the title compound (88 mg, 80%). LCMS (ES) [M+1]+m/z 424.1.

Example 114

Synthesis of 1-[3-({8-methoxy-2,2-dimethyl-4-phenyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl}oxy)propyl]pyrrolidine formate

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl} oxy)-propyl]pyrrolidine (Intermediate 111-2) and phenylboronic acid, following a procedure similar to that described above in Example 83. The volatiles were removed under reduced pressure and the residue was re-dissolved in DMSO, filtered and purified. subjected to preparative reverse-phase HPLC purification (Prep-C18 XSelect column, 5 ^M, 19 x 150 mm, Waters; gradient elution of 10-50% MeCN in water over a period of 20 min, in which both solvents contain 0.1% hydrochloric acid) to give the title compound as a yellow solid. LCMS (ES) [M+1]+ m/z 432.1.

Example 115

Synthesis of N-[(2,4-dimethoxyphenyl)methyl]-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-formate amine

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta-[c]quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate II -1) and (2,4-dimethoxyphenyl)methanamine, following a procedure similar to that described in Example 3 above, except that the reaction mixture was allowed to stir at 140 °C under a N2 atmosphere for 1.5 h. The crude mixture was treated with water and the volatiles were removed under reduced pressure. The residue was re-dissolved in DMSO, filtered and subjected to preparative reverse-phase HPLC (Prep-C18 column, XBridge 5 ^M, 19 x 150 mm, Waters; gradient elution from 0-40% MeCN in water for a period of 20 min, in which both solvents contain 0.1% formic acid (FA)) to give the title compound as a white solid. LCMS (ES) [M+1]+ m/z 492.1.

Example 116

Synthesis of 8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cidopenta[c]quinolin-4-amine formate

A mixture of N-[(2,4-dimethoxyphenyl)methyl]-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4 formate -amine (Example 115. 228 mg, 0.46 mmol) in TFA (0.5 mL) and ChCl3 (0.8 mL) was left under stirring at 70 °C for 1.5 hours. Organic volatiles were removed under reduced pressure and the residues were dissolved in DMSO, filtered off and subjected to preparative reverse-phase HPLC (Prep-C18 column, XBridge 5 ^M, 19 x 150 mm, Waters; gradient elution of 0-40% MeCN in water over a period of 20 min, where both solvents contain 0.1% formic acid (FA)) to give the title compound as a white solid. LCMS (ES) [M+1]+ m/z 342.1.

Example 117

Synthesis of N-[(2,4-dimethoxyphenyl)methyl]-8-methoxy-2,2-dimethyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[ c]quinolin-4-amine

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl] pyrrolidine (Intermediate II-4) and (2,4-dimethoxyphenyl)methanamine, following a procedure similar to that described above in Example 115. The crude mixture was treated with water and the volatiles were removed under reduced pressure. The residue was re-dissolved in DMSO, filtered and subjected to preparative reverse-phase HPLC (Prep-C18 column, XBridge 5 ^M, 19 x 150 mm, Waters; gradient elution from 0-40% MeCN in water over a period of 20 min, where both solvents contain 0.1% formic acid (FA)) to give the title compound as a white solid. LCMS (ES) [M+1]+ m/z 520.1.

Example 118

Synthesis of 8-methoxy-2,2-dimethyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine formate

The title compound was prepared from N-[(2,4-dimethoxyphenyl)methyl]-8-methoxy-2,2-dimethyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H formate ,2H,3H-cyclopenta[c]quinolin-4-amine (Example 117) following a procedure similar to that described above in Example 116. The crude mixture was treated with water and the volatiles were removed under reduced pressure. Organic volatiles were removed from the crude reaction mixture under reduced pressure and the residues were dissolved in DMSO, filtered off and subjected to preparative reverse-phase HPLC (Prep-C18 column, XBridge 5 ^M, 19 x 150 mm , Waters; gradient elution from 0-40% MeCN in water over a period of 20 min, where both solvents contain 0.1% formic acid (FA) to give the title compound as a white solid. LCMS (ES) [M+1]+ m/z 370.1.

Example 119

Synthesis of 3-({8-m ethoxy-7-[3-(pyrroNdin-1-N)propoxy]-1H,2H,3H-ddopenta[c]quinoNn-4-N}am ino)propane nitrile formate

The title compound was prepared from 1-[3-({4-doro-8-methoxMH,2H,3H-ddopenta[c]-quinolin-7-N}oxy)propN]pyrrolidine (Intermediate II-1 ) and 3-aminopropanenitrile, (2E)-but-2-enedioic acetate, following a procedure similar to that described in Example 3 above, except that BuONa was used in 10.0 equivalents. The crude product was treated with water and the volatile organic compounds were removed under reduced pressure. Residues were redissolved in DMSO, filtered off and subjected to preparative reverse-phase HPLC (Prep-C18 column, 5 pM OBD, 19*250 mm, Waters; 0-25 % MeCN gradient elution in water over a period of 20 min, both solvents containing 0.1% formic acid, flow rate: 20 mL/min) to give the title compound as a brown syrup. LCMS (ES) [M+1] m/z 395.2.

Example 120

Synthesis of 8-methoxy-N-[2-(methylsulfanyl)ethyl]-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine formate

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate II -1) and 2-(methylsulfanyl)ethanamine, following a procedure similar to that described above in Example 3, except that the reaction mixture was allowed to stir at 140 °C under a N2 atmosphere for 1.5 h. The crude product was treated with water and the volatile organic compounds were removed under reduced pressure. Residues were redissolved in DMSO, filtered off, and subjected to preparative reverse-phase HPLC (Prep-C18 column, 5 pM OBD, 19*250 mm, Waters; 0-40% MeCN gradient elution in water over a period of 20 min, both solvents containing 0.1% formic acid, flow rate: 20 mL/min) to give the title compound as a pale yellow solid. LCMS (ES) [M+1]+ m/z 416.2.

Example 121

Synthesis of (1S,3R)-3-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)cyclohexane -1-ol and (1R,3S)-3-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl} amino)cyclohexan-1-ol (1:1 mixture as formate salt) and (1R,3R)-3-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy] formate -1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)cyclohexan-1-ol and (1S,3S)-3-({8-methoxy-7-[3-(pyrrolidin-1-yl )propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)cyclohexan-1-ol (1:1 mixture as formate salt)

(Mix 1:1 as formate salt) (Mix 1:1 as formate salt)

The title compounds as two pairs of 1:1 mixtures as the formate salt, were prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]- quinoline-7-yl}oxy)propyl]pyrrolidine (Intermediate Compound II-1) and 3-aminocyclohexanol, following a procedure similar to that described above in Example 3, except that the reaction mixture was allowed to stir at 140 °C under N2 atmosphere for 1.5 h. The crude product was treated with water and volatile organic compounds were removed under reduced pressure. Residues were redissolved in DMSO, filtered off and subjected to preparative reverse-phase HPLC (Prep-C18 column, 5 ^M OBD, 19 x 250 mm, Waters; MeCN gradient elution 0-25 % in water over a period of 20 min, where both solvents contain 0.1% formic acid, flow rate: 20 mL/min) to provide two fractions with the desired mass of LCMS (ES) [M+1]+m/ z 440.2. Among them, the fraction that came out first from the column was a 1:1 mixture of two isomers, LCMS (ES) [M+1]+m/z 440.2, which was one of the two title mixtures; the second fraction coming off the column was a 1:1 mixture of two isomers, LCMS (ES) [M+1]+m/z 440.2, which was the other of the two title mixtures.

Example 122

Synthesis of (1S,2S)-2-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}ammonium formate )cyclohexane-1-ol

The title compounds were prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate II -1) and (1R,2R)-2-aminocyclohexanol, following a procedure similar to that described above in Example 3, except that the reaction mixture was allowed to stir at 130 °C under a N2 atmosphere for 1.5 h. The crude product was treated with water and the volatile organic compounds were removed under reduced pressure. Residues were redissolved in DMSO, filtered off and subjected to preparative reverse-phase HPLC (Prep-C18 column, 5 ^M OBD, 19 x 250 mm, Waters; MeCN gradient elution 0-25 % in water over a period of 20 min, where both solvents contain 0.1% formic acid, flow rate: 20 mL/min) to give the title compound as a white solid. LCMS (ES) [M+1]+ m/z 440.2.

Example 123

Synthesis of (1R,4R)-4-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino formate )cyclohexane-1-ol

The title compounds were prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate II -1) and trans-4-aminocyclohexan-1-ol, following a procedure similar to that described above in Example 3, except that the reaction mixture was allowed to stir at 130 °C under N2 atmosphere for 1.5 h. The crude product was treated with water and the volatile organic compounds were removed under reduced pressure. Residues were redissolved in DMSO, filtered off and subjected to preparative reverse-phase HPLC (Prep-C18 column, 5 ^M OBD, 19 x 250 mm, Waters; MeCN gradient elution 0-25 % in water over a period of 20 min, where both solvents contain 0.1% formic acid, flow rate: 20 mL/min) to give the title compound as a white solid. LCMS (ES) [M+1] m/z 440.2.

Example 124

Synthesis of (1S,2S)-2-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}ammonium formate ) cyclopentane-1-ol

The title compounds were prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate II -1) and (1R,2R)-2-aminocyclopentan-1-ol, following a procedure similar to that described above in Example 3, except that the reaction mixture was allowed to stir at 140 °C under an N2 atmosphere for 1.5 h. The crude product was treated with water and the volatile organic compounds were removed under reduced pressure. Residues were redissolved in DMSO, filtered off and subjected to preparative reverse-phase HPLC (Prep-C18 column, 5 ^M OBD, 19 x 250 mm, Waters; MeCN gradient elution). 0-25 % in water over a period of 20 min, where both solvents contain 0.1% formic acid, flow rate: 20 mL/min) to give the title compound as a yellow solid. LCMS (ES) [M+1]+ m /z 426.1. Example 125

Synthesis of a mixture (1:1) of (1R,2S)-2-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinoln -4-yl} amino)cyclopentane-1 -ol and (1S,2R)-2-({8-methoxy-7-[3-(pyrrolidin-1 -yl)propoxy]-1H,2H,3H-cyclopenta[ c]quinolin-4-yl}amino)cyclopentan-1-ol as formate salt

Mix 1:1 in the form of formate salt

The title compounds, as a 1:1 mixture as the formate salt, were prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin -7-yl}oxy)propyl]pyrrolidine (Intermediate II-1) and cis-2-aminocyclopentan-1-ol, following a procedure similar to that described above in Example 3, except that the reaction mixture was allowed to stir at 140 °C under N2 atmosphere for 1.5 h. The crude product was treated with water and the volatile organic compounds were removed under reduced pressure. Residues were redissolved in DMSO, filtered off, and subjected to preparative reverse-phase HPLC (Prep-C18 column, 5 pM OBD, 19 x 250 mm, Waters; 0-25% MeCN gradient elution). in water over a period of 20 min, where both solvents contain 0.1% formic acid, flow rate: 20 mL/min) to give the title compounds as a mixture as a yellow solid. LCMS (ES) [M+1]+ m/z 426.1.

Example 126

Synthesis of 3-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)cyclopentan-1-formate hey

The title compound was prepared from 1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine (Intermediate II -1) and 3-aminocyclopentan-1-ol following a procedure similar to that described above in Example 3, except that the reaction mixture was allowed to stir at 140 °C under N2 atmosphere for 1.5 h. The crude product was treated with water and the volatile organic compounds were removed under reduced pressure. Residues were redissolved in DMSO, filtered off, and subjected to preparative reverse-phase HPLC (Prep-C18 column, 5 pM OBD, 19 x 250 mm, Waters; 0-25% MeCN gradient elution). in water over a period of 20 min, both solvents containing 0.1% formic acid, flow rate: 20 mL/min) to give the title compound as a yellow solid. LCMS (ES) [M+1]+ m/z 426.1. biological examples

Example 1

Determination of G9a enzymatic activity assay

The G9a AlphaLISA assay was used to detect methyl modifications of a biotinylated histone H3 peptide by the compounds. These modifications are carried out by the activity of the histone methyl transferase enzyme G9a. The assay consists of reading a chemiluminescent signal at 615 nm; this signal is generated by laser excitation at 680nm which transfers a reactive singlet oxygen between the donor beads and the acceptor beads. The donor beads are conjugated to streptavidin and bind to the biotin on the peptide. The acceptor beads are conjugated to an antibody that recognizes the G9a-specific methyl tag on the peptide. If there is a methyl tag on the peptide, the acceptor beads will bind to the peptide. Upon binding, the acceptor beads will be in close proximity (<200nm) to the donor beads and when the donor beads are excited, oxygen transfer can occur and a strong signal will be generated. If there is no methyl label, interaction between the beads will not occur and the signal will be at background levels.

For the assay, the following buffer was used to prepare the reactions: 50 mM Tris-HCl pH 9, 50 mM NaCl, 0.01% Tween-20, and 1 mM DTT (added fresh before starting reactions). The assay is prepared by adding a final concentration of 0.15 nM G9a, 15 pM S-adenosyl-methionine, and 100 nM biotinylated histone 3 peptide (1-21). The The reaction is incubated at room temperature for 1 hour and subsequently quenched by the addition of acceptor beads (AlphaLISA anti-H3k9me2 acceptor beads, PerkinElmer #AL117) to a final concentration of 20 pg/mL. Acceptor beads are incubated for 1 hour. After 1 hour, donor beads are added to a final concentration of 20 pg/ml (alpha streptavidin donor beads, PerkinElmer #6760002). Donor beads are incubated for 0.5 hours. Both donor and acceptor beads are resuspended in the AlphaLISA 5X Epigenetics Buffer 1 Kit (PerkinElmer #AL008) before being added to the reaction. All manipulations and incubations with the donor and acceptor beads are performed in dim light. The signal is detected on an EnVision plate reader in Alpha mode (see ACS Med Chem Lett. 2014 Jan 2; 5(2): 205-9. doi: 10.1021/ml400496h. eCollection 2014. Discovery and development of potent and selective inhibitors of histone methyltransferase g9a.)

Percent inhibition was calculated for each compound dilution and the concentration that produced 50% inhibition was calculated. This value is presented as the IC50. IC50 values for a representative number of compounds of the disclosure are provided below.

Table A

Example 2

Fetal Hemoglobin Induction Assay

Cryopreserved hematopoietic bone marrow CD34+ cells obtained from healthy adult human donors were used for all studies. A 21-day ex vivo serum-free culture system consisting of two phases was used. In culture phase I (culture days 1-7), CD34+ cells were placed in medium containing StemPro-34 complete medium (1-glutamine, pen-strep, and StemPro-34 nutrient supplement) (Invitrogen, Carlsbad, CA) supplemented with 50 ng/ml SCF (HumanZyme, Chicago, IL), 50 ng/ml FLT3 ligand (HumanZyme), and 10 ng/ml IL-3 (HumanZyme). During the first phase of culture (days 0-7), CD34+ cells differentiate into progenitor cell populations that include erythroblasts. After 7 days, cells were transferred to erythropoietin (EPO; Stemcell)-supplemented medium (phase 2; culture days 7-21) consisting of the following: StemPro-34 complete medium, 4 U/ml EPO, mifepristone 3 pM (Sigma Aldrich, St. Louis, MO), 10 pg/ml insulin (Sigma Aldrich), 3 U/ml heparin (Sigma Aldrich), and 0.8 mg/ml holotransferrin (Sigma Aldrich). Compounds are added during phase 2; days 7-21 to assess fetal hemoglobin production (see Blood. 2015 Jul 30; 126(5): 665-72. Inhibition of G9a methyltransferase stimulates fetal hemoglobin production by facilitating CSF loop formation /Y-globin).

The expression levels of the α, p, and y globin genes are assessed by quantitative PCR analysis. HbF protein levels are assessed using the human hemoglobin F enzyme-linked immunosorbent assay (ELISA) quantitation kit (Bethyl Laboratory, Montgomery, TX, USA). The percentages of cells expressing HbF are evaluated by flow cytometry analysis. Briefly, RNA samples were prepared and complementary DNA synthesized, according to the manufacturer's instructions (Qiagen, Germany). qRT-PCR analysis of human globin genes was performed with the TaqMan Gene Expression Master.

Formulation Examples

The following are representative pharmaceutical formulations containing a compound of the present disclosure.

Tablet Formulation

The following ingredients are mixed intimately and pressed into individual scored tablets.

Ingredient Amount per tablet mg

composed of this disclosure 400

corn starch 50

croscarmellose sodium 25

lactose 120

magnesium stearate 5

Capsule Formulation

The following ingredients are intimately mixed and filled into a hard shell gelatin capsule.

Ingredient Quantity per capsule mg

composed of this disclosure 200

dehydrated lactose 148

magnesium stearate 2

injectable formulation

Disclosure compound (eg, compound 1) in 2% HPMC, 1% Tween 80 in DI water, pH 2.2 with MSA, sufficient to at least 20 mg/mL.

Composition for inhalation

To prepare a pharmaceutical composition for administration by inhalation, 20 mg of a compound disclosed herein is mixed with 50 mg of anhydrous citric acid and 100 ml of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation administration unit, such as a nebulizer, which is suitable for administration by inhalation.

Topical gel composition

To prepare a pharmaceutical topical gel composition, 100 mg of a compound disclosed herein is mixed with 1.75 g of hydroxypropylcellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate, and 100 mL of USP purified alcohol. The resulting gel mixture is then incorporated into containers, such as tubes, that are suitable for topical administration.

Composition of the ophthalmic solution

To prepare a pharmaceutical ophthalmic solution composition, 100 mg of a compound disclosed herein is mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic administration units, such as eye drop containers, which are suitable for ophthalmic administration.

nasal spray solution

To prepare a pharmaceutical nasal spray solution, 10 g of a compound disclosed herein is mixed with 30 ml of a 0.05 M phosphate buffer solution (pH 4.4). The solution is placed in a nasal dispenser designed to deliver 100 pL of aerosol per spray.

Claims (24)

1. A compound of formula (I):

in which: Z1 and Z2 are independently C (when R2 or R3 are attached to them), CH, or N; alk is alkylene in which one or two carbon atoms of the alkylene chain are optionally replaced by NR, O, S or SO2 (where R is hydrogen or alkyl), and the alkylene chain is substituted by one or two substituents independently selected from halo, haloalkyl, haloalkoxy, hydroxy, and alkoxy, and wherein -alk-R1 is attached to carbon (a) or (b); where alk in -(alk)-R1 is -(CH2)2-*, -(CH2)3-*, -(CH2)4-*, -CH2CH(CH3)CH2-*, *-CH2CH(CH3 )CH -, -O-(CH2)-*, -O-(CH2)2-*, -O-(CH2)3-*, -OCH2CH(F)CH2-*, -OCH2CH(OCH3)CH2-* , or -OCH2CH(OCF3)CH2-*, where * indicates the point of attachment to -R1; R1 is -NR6R7 (wherein R6 and R7 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl or haloalkoxyalkyl), unsubstituted heterocyclyl, heterocyclyl substituted with 1, 2 or 3 of Ra, Rb and Rc where Ra, Rb and Rc are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, alkylcarbonyl, and haloalkylcarbonyl, or spiroheterocycloamino in which a nitrogen atom of the spiroheterocycloamino is bonded to alk; R2 is hydrogen, alkyl, cycloalkyl, halo, hydroxy, alkoxy, haloalkoxy, or cyano; R3 is hydrogen, alkyl, halo, alkoxy, alkylamino, dialkylamino, or cyano; R4 is alkyl (optionally substituted with one to nine deuterium), or NReRf (where Re is hydrogen or alkyl and Rf is hydrogen, alkyl, deuterated alkyl, alkylthioalkyl, acyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cyanoalkyl, carboxyalkyl, alkoxycarbonylalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl), wherein cycloalkyl, aryl, heteroaryl, and heterocyclyl alone or as part of cycloalkylalkyl, aralkyl, heteroaralkyl, and heterocyclylalkyl at Rf is unsubstituted or substituted with 1, 2, or 3 of Rg, Rh, and Ri, wherein Rg, Rh, and Ri are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, cyano, carboxy, alkoxycarbonyl, and haloalkoxy, and wherein the alkylene of the aralkyl, heteroaralkyl, heterocyclylalkyl, and cycloalkylalkyl at Rf is optionally substituted with one to nine deuteriums; X is carbon or nitrogen; Y ring B is phenyl, 5- or 6-membered cycloalkyl, spirocycloalkyl, spiroheterocycloamino, or saturated 5-, 6-, or 7-membered heterocyclyl, wherein each of the ring(s) of ring B is unsubstituted or substituted with 1, 2, 3 or 4 of Rj, Rk, R1 and Rm wherein Rj, Rk, R1 and Rm are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl and haloalkoxy; or one of its pharmaceutically acceptable salts. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring B is unsubstituted 5 or 6 membered cycloalkyl or 5 or 6 membered cycloalkyl substituted with 1, 2, 3 or 4 of Rj , Rk, R1 and Rm where Rj, Rk, R1 and Rm are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl and haloalkoxy. 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring B is an unsubstituted 5-, 6-, or 7-membered saturated heterocyclyl or a 5-, 6-, or 7-membered saturated heterocyclyl substituted with 1 , 2, 3 or 4 of Rj, Rk, R1 and Rm wherein Rj, Rk, R1 and Rm are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl and haloalkoxy. 4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Z1 and Z2 are independently C or CH. 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein -alk-R1 is attached to carbon (a) and R2 is attached to carbon (b). 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R1 is -NR6R7, wherein -NR6R7 is amino, methylamino, ethylamino, dimethylamino, or diethylamino. 7. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R1 is an unsubstituted heterocyclyl or a heterocyclyl substituted with 1, 2 or 3 of Ra, Rb and Rc wherein Ra, Rb and Rc are independently selected from alkyl, hydroxy, alkoxy and halo. 8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R2 is alkyl, halo, or alkoxy. 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R4 is alkyl, preferably methyl. 10. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R4 is NReRf (where Re is hydrogen or alkyl, and Rf is hydrogen, alkyl, acyl, haloalkyl, hydroxyalkyl , alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl), wherein cycloalkyl, aryl, heteroaryl, and heterocyclyl alone or as part of cycloalkylalkyl, aralkyl, heteroaralkyl, and heterocyclylalkyl at Rf are unsubstituted or substituted with 1, 2 or 3 of Rg, Rh and Ri, where Rg, Rh and Ri are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, cyano, carboxy, alkoxycarbonyl and haloalkoxy. 11. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R4 is NReRf (where Re is hydrogen or alkyl, and Rf is alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl , aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl), wherein cycloalkyl, aryl, heteroaryl, and heterocyclyl alone or as part of cycloalkylalkyl, aralkyl, heteroaralkyl, and heterocyclylalkyl at Rf are unsubstituted or substituted with 1, 2 or 3 of Rg, Rh and Ri where Rg, Rh and Ri are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, cyano, carboxy, alkoxycarbonyl and haloalkoxy. 12. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R4 is -NH-alkyl or -N(alkyl)-alkyl, preferably R4 is -NH-methyl, -NH-ethyl, -NH -n-propyl, -NH-isopropyl, -N(methyl)(isopropyl), -NH-n-butyl, -NH-isobutyl, -NH-tert-butyl, -NH-*CH(CH3)CH2CH3 (in the where *C is (R) or (S)), or NH-pentyl (all isomers), more preferably NH-methyl, -NH-ethyl, -NH-n-propyl or -NH-isopropyl. 13. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R4 is -NRecycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 or 2 of Rg and Rh independently selected from alkyl, hydroxy , alkoxy, cyano, halo, haloalkyl and haloalkoxy, preferably R4 is -NH-cyclopropyl, -NH(1-methylcyclopropyl), -NH(1-cyanocyclopropyl), -NH(2-cyanocyclopropyl), -NH-cyclobutyl, -NH (3-hydroxycyclobutyl), -NH-cyclopentyl, -N(methyl)(cyclopentyl), -NH-cyclohexyl, -NH-(3-fluorocyclobutyl), -NH-(3,3-difluorocyclobutyl), or -NH-(3 ,3-dimethylcyclobutyl), more preferably -NH-cyclopropyl, -NH-cyclopentyl or -NH-cyclohexyl. 14. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R4 is -NH-heterocyclyl, wherein heterocyclyl is unsubstituted or substituted with 1, 2 or 3 of Rg, Rh and Ri wherein Rg, Rh and Ri are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl and haloalkoxy, preferably R4 is -NH-piperidin-4-yl, -NH-tetrahydropyran-4-yl, -NH-oxetan- 3-yl, -NH-tetrahydrofuran-3-yl, -NH-(2,6-dimethyltetrahydropyran-4-yl), or -NH-(1-alkylpiperidin-4-yl). 15. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R4 is -NH-cycloalkylalkyl, wherein the cycloalkyl of the cycloalkylalkyl is unsubstituted or substituted with 1 or 2 of Rg and Rh in the that Rg and Rh are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl and haloalkoxy, preferably R4 is -NH-CH2-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 or 2 of Rg or Rh in wherein Rg and Rh are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl and haloalkoxy, more preferably R4 is -NH-CH2-cyclopropyl, -NH-*CH(CHa)cyclopropyl (wherein *C is (R ) or (S)), -NH-CH2-cyclobutyl, -NH-*CH(CHa)cyclobutyl (where *C is (R) or (S)), -NH-cH2-cyclopentyl, -NH-CH2 -cyclohexyl, -NH-CH2-(3-fluorocyclobutyl), -NH-CH2-(3,3-difluorocyclobutyl), -NH-CH2-(3,3-dimethylcyclobutyl), -NH-CH2-(1-methylcyclopropyl) , -NH-CH2-(1-methylcyclobutyl), -NH-(CH2)2-cyclopropi lo, -NH-(CH2)2-cyclopentyl or -NH-(CH2)2-cyclohexyl, even more preferably -NH-CH2-cyclopropyl or -NH-CH2-cyclobutyl. 16. The compound of claim 10, or a pharmaceutically acceptable salt thereof, where R4 is -NH-(hydroxyalkyl) or -NH-(alkoxyalkyl), preferably R4 is -NH-(2-hydroxyethyl),-NH-( 2-hydroxybutyl), -NH-(2-hydroxy-2-methylpropyl), -NH-(2-methoxyethyl), -NH-(2-methoxypropyl), -NH-(2-methoxy-2-methylpropyl), or -NH -(2-methoxybutyl). 17. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R4 is -NH-heterocyclylalkyl, wherein the heterocyclyl of heterocyclylalkyl is unsubstituted or substituted with 1, 2 or 3 of Rg, Rh and Ri where Rg, Rh and Ri are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl and haloalkoxy, preferably R4 is -NH-CH2-oxetan-3-yl, -NH-CH2-piperidin-4-yl , -NH-CH2-tetrahydropyran-4-yl, -NH-CH2-tetrahydrofuran-3-yl, -NH-CH2-(1-alkylpiperidin-4-yl), -NH-(CH2)2-oxetan-3- yl, -NH-(CH2)2-piperidin-4-yl, -NH-(CH2)2-tetrahydropyran-4-yl, -NH-(cH2)2-tetrahydrofuran-3-yl, or -NH-(CH2 )2-(1-alkylpiperidin-4-yl). 18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen. 19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound, or the pharmaceutically acceptable salt thereof, is selected from

or a parent compound of any of the salts shown above, or a pharmaceutically acceptable salt of the parent compound. 20. A pharmaceutical composition comprising a compound of any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient. 21. A compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, for use in a method of inhibiting G9a to treat cancer or an autoimmune or inflammatory disease. 22. A compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 20 for use in a method of ameliorating and/or treating a hemoglobinopathy, wherein the hemoglobinopathy is sickle cell disease or beta-thalassemia. 23. A compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 20, for use in a method of ameliorating and/or treating a cancer, wherein the cancer selected from: colorectal cancer, osteosarcoma cancer, acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); adrenocortical carcinoma, Kaposi's sarcoma (soft tissue sarcoma); an AIDS-related lymphoma (lymphoma); a primary CNS lymphoma; an anal cancer; a gastrointestinal carcinoid tumor; an astrocytoma; an atypical teratoid/rhabdoid tumor; a basal cell carcinoma of the skin; a cancer of the bile ducts; bladder cancer; a bone cancer (includes Ewing's sarcoma and osteosarcoma and malignant fibrous histiocytoma); a brain tumor; a breast cancer; a bronchial tumor, a Burkitt's lymphoma; a heart tumor; an embryonal tumor (brain cancer); a germ cell tumor (brain cancer); a primary CNS lymphoma; cervical cancer; a cholangiocarcinoma; a chordoma; a chronic lymphocytic leukemia (CLL); a chronic myelogenous leukemia (CML); a chronic myeloproliferative neoplasm; a craniopharyngioma (brain cancer); a cutaneous T-cell lymphoma; a ductal carcinoma in situ (DCIS); endometrial cancer (uterine cancer); an ependymoma (brain cancer); an esophageal cancer; an esthesioneuroblastoma; Ewing's sarcoma (bone cancer); extracranial germ cell tumor; extragonadal germ cell tumor; eye cancer; intraocular melanoma; a retinoblastoma; fallopian tube cancer; a fibrous histiocytoma of bone; gallbladder cancer; a gastric (stomach) gastrointestinal stromal tumor (GIST) (soft tissue sarcoma); a CNS germ cell tumor (brain cancer); an extracranial germ cell tumor; an extragonadal germ cell tumor; an ovarian germ cell tumor; testicular cancer; gestational trophoblastic disease; a hairy cell leukemia; head and neck cancer; hepatocellular (liver) cancer; a histiocytosis, a Langerhans cell; Hodgkin's lymphoma; hypopharyngeal cancer (cancer of the head and neck); an intraocular melanoma; an islet cell tumor; a pancreatic neuroendocrine tumor; kidney (renal cell) cancer; a Langerhans cell histiocytosis; cancer of the larynx (cancer of the head and neck); a leukemia; a cancer of the lip and oral cavity (cancer of the head and neck); lung cancer (non-small cell and small cell); a lymphoma; a male breast cancer; a melanoma; a Merkel cell carcinoma (skin cancer); a mesothelioma; a malignant mesothelioma; metastatic squamous cell carcinoma of the neck with an occult primary (head and neck cancer); a midline tract carcinoma involving the NUT gene; mouth cancer (cancer of the head and neck); multiple syndromes of endocrine neoplasia; multiple myeloma/plasma cell neoplasms; a mycosis fungoides (lymphoma); a myelodysplastic syndrome, a myelodysplastic/myeloproliferative neoplasm; a cancer of the nasal cavity and paranasal sinus (cancer of the head and neck); a cancer of the nasopharynx (cancer of the head and neck); a nasopharyngeal cancer - neuroblastoma; a non-Hodgkin's lymphoma; an oral cancer; lip and oral cavity cancer and oropharyngeal cancer (cancer of the head and neck); ovarian cancer; pancreatic cancer; a papillomatosis; a paraganglioma; a cancer of the paranasal sinus and nasal cavity (cancer of the head and neck); parathyroid cancer; penile cancer; to pharyngeal cancer (cancer of the head and neck); a pheochromocytoma; a pituitary tumor; a pleuropulmonary blastoma; a primary CNS lymphoma; a primary peritoneal cancer; prostate cancer; a rectal cancer; a rhabdomyosarcoma (soft tissue sarcoma); salivary gland cancer (head and neck cancer); a salivary gland tumor; a vascular tumor (soft tissue sarcoma); a uterine sarcoma; a Sezary syndrome (lymphoma); small intestine cancer; a squamous cell carcinoma; a skin cancer; a squamous cell cancer of the neck with an occult primary, metastatic (cancer of the head and neck); a cutaneous T-cell lymphoma; throat cancer (head and neck cancer); a nasopharyngeal cancer; an oropharyngeal cancer; hypopharyngeal cancer; a thymoma and a thymic carcinoma; to thyroid cancer; urethral cancer; a vaginal cancer; a vascular tumor (soft tissue sarcoma); vulvar cancer; a myelodysplastic syndrome (MDS); and a Wilms tumor. 24. A compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 20, for use in a method of ameliorating and/or treating an autoimmune or inflammatory disease, in the that the autoimmune or inflammatory disease is selected from: arthritis, atherosclerosis, multiple sclerosis, myasthenia gravis, Crohn's disease, graft versus host disease, psoriasis, granulomatous colitis, lymphocytic colitis, collagenous colitis, ulcerative colitis, celiac disease, subepidermal blistering disorders systemic lupus erythematosus, discoid lupus erythematosus, cutaneous lupus, dermatomyositis, polymyositis, Sjogren's syndrome, primary biliary cirrhosis, chronic active hepatitis, chronic fatigue syndrome vasculitis, and systemic sclerosis.